KR20010085332A - Treatment of addiction and addition-related behavior - Google Patents

Abstract

The present invention provides a method for altering the addiction-related behavior of a mammal suffering from an abuse drug addiction. The method comprises administering to the mammal an effective amount of gamma-vinyl GABA (GVG), or a pharmaceutically acceptable salt, enanthiomer or racemic mixture thereof, sufficient to reduce, inhibit or eliminate the behavior associated with the craving or use of an abuse drug ≪ / RTI >

Description

[0002] TREATMENT OF ADDICTION AND ADDITION-RELATED BEHAVIOR [0003]

Substance addiction can occur through the use of legitimate and illegal substances. Nicotine, cocaine, amphetamines, methamphetamine, ethanol, heroin, morpholine, and other addictive substances are readily available and routinely used by the majority of Americans.

Many abuse drugs exist naturally. For example, cocaine is a naturally occurring non-amphetamine stimulant obtained from the leaves of a coca plant (Erythroylon coca). Coca leaves contain about 0.5% pure cocaine alkaloids. When chewed, only a relatively modest amount of cocaine is liberated and absorption into the intestines is slow. Therefore, it can be seen why chewing coca leaves in Latin America has not been a public health problem.

Addictive drugs such as nicotine, cocaine, amphetamine, meta-amphetamine, ethanol, heroin and morphine may directly enhance dopamine (DA) in some cases, or indirectly in other cases, Or even by trans-synaptically enhancing the synapses, resulting in enhanced brain compensation that is high on the drug addict. In addition, changes in the action of the DA system were closely related to the recurrence of drug craving and drug intake habits in restoring the addicts. For example, cocaine binds to the dopamine transporter (DAT) and acts on the DA system by interfering with the DA uptake into the presynaptic terminal.

There is much evidence that nicotine, cocaine, amphetamines, methamphetamine, ethanol, and other addictive drug addictions are associated with inhibition of reuptake of the compensatory / enhancing pathway of the central nervous system (CNS). For example, in the case of rodents, the increase of extracellular DA by cocaine was found to increase the compensation and craving action of DA. In humans, from the pharmacokinetic profile of ¹¹ C-cocaine, it can be seen that the inhalation of the labeled cocaine is directly related to the self-reported "intoxication". In addition, cocaine addicts exposed to cocaine-related environments or stimuli will have increased cocaine craving neutralized by haloperidol, an antagonist of the DA receptor. Thus, on the basis of the relationship between cocaine addiction and the DA compensation / enhancement circuit of the anterior cerebral cortex, many pharmacological methods have been proposed for treating cocaine poisoning.

In the past, one method was to inhibit cocaine binding by directly targeting DAT using high-affinity cocaine analogs. Another treatment was direct control of synaptic DA using DA antagonists or agonists. Another method of treatment was to control synaptic DA indirectly, or across synapses, by specifically targeting a biochemically different neurotransmission system, which is functionally related.

A number of drugs have been proposed to break cocaine-based self-contained cocaine. Certain treatments were preferred in terms of "dopamine depletion hypothesis". It is well known that cocaine interferes with dopamine reuptake and actually increases synaptic dopamine concentration. However, in the presence of cocaine, synaptic dopamine is metabolized and secreted in the form of 3-methoxythiamine. As demonstrated by the increased activity of tyrosine hydroxylase following administration of cocaine, increased dopamine synthesis is required in the human body due to the synaptic loss of dopamine. When the precursor is completely consumed, a deficiency of dopamine occurs. Based on this hypothesis, bromocriptine, an agonist of the dopamine receptor, was tested. Another method was to administer amantadine, a dopamine releasing agent. Another method based on the hypothesis of dopamine depletion was to provide dopamine excreta such as L-dopa.

Agents are not the preferred therapeutic agents. Certain agonists may act on some receptors, or similar receptors may act on different cells that are not specific receptors or cells for which stimulation is desired. Resistance to drugs occurs through changes in the number of receptors and the affinity of the receptor for the drug, so resistance to the agent may occur. For example, the problem with bromocriptine, an agonist, is that it can cause drug dependence. Thus, the treatment methods used in the past did not reduce the patient's desire for cocaine. In addition, patients use a specific agonist, such as bromocriptine, so they can crave something else.

Another commonly abused drug is nicotine. Alkaloid (-) - nicotine is present in cigarettes or other tobacco products that chew or chew. Nicotine has been shown to cause a variety of diseases, especially heart disease, including cancer, heart disease, respiratory disease, and other conditions where the use of tobacco is a risk.

A number of unpleasant withdrawal symptoms, including irritation, anxiety, insomnia, lack of concentration, head lightness, trembling, increased hunger and weight gain, and a strong craving for tobacco, have been performed in vigorous exercise against the use of tobacco or nicotine Is known to occur.

Nicotine intoxication has been shown to be involved in the action of the DA neurons in the compensatory / enhancing and brain compensatory pathways (Nisell et al., 1995; Pontieri, et al., 1996). For example, acute systemic administration of nicotine and a number of other abuse drugs increases the extracellular DA level of the nucleus accumbens (NACC), an important component of the compensatory system (Damsma et al., 1989; Di Chiara and Imperato, 1989; Imperato et al., 1986; Nisell et al., 1994a, 1995; Pontieri et al., 1996). Likewise, injecting nicotine into the abdominal region of the animal (VTA) of the ruminant significantly increases the DA level in the NACC (Nisell et al., 1994b).

Several drugs have been reported to be useful for treating nicotine dependence, including nicotine replacement therapy, such as bupropion, as the first non-nicotine therapy for nicotine gum, transdermal nicotine patch, nasal spray, nicotine inhaler and smoking cessation (Henningfield, 1995 ; Hurt et al., 1997).

Unfortunately, nicotine replacement therapy often requires the administration of nicotine, which causes withdrawal and re-use of tobacco products. Thus, there is a need for a treatment with desirable side effects to reduce withdrawal, including long-term craving for nicotine.

Other well known addictive agents are narcotic analgesics such as morphine, heroin and natural and semisynthetic opioids. Abuse of opioids causes tolerance and dependence. The severity of withdrawal from the interruption of an opioid can vary greatly depending on a number of factors, including the amount of opioid used, the extent to which the effect of the opioid on the CNS is continuous, the duration of chronic use, and the rate at which the opioid is removed from the receptor can do. These withdrawal symptoms include, but are not limited to, aches, anxiety, discomfort, tiredness, sweating, yurus, bruising, insomnia, irritability, student obesity, bones, back and muscle tingling, hot and cold flashes, nausea, vomiting, diarrhea, Increased blood pressure, increased pulse and respiration rate, muscle cramps, and stimulation of the legs.

Medical complications associated with the injection of opioids include a number of pathologic changes of the CNS, including degenerative changes of the pale nucleus, gangrene gray matter retention, transverse myelitis, amblyopia, peripheral neuropathy, Parkinson's syndrome, And pathological changes in muscle and peripheral nerves. Also, skin and systemic infections are very common, including staphylococcal pneumonia, tuberculosis, endocarditis, sepsis, viral hepatitis, human immunodeficiency virus (HIV), malaria, tetanus and osteomyelitis. Over-dosing, drug-related infections, suicide, and murder have significantly reduced the average life expectancy of opioid addicts.

Agents used to treat opioid dependence include methadone, an opioid, and opioid antagonists (naloxone and naltrexone). Clonidine suppresses some of the elements of opioid withdrawal but has been found to have side effects of hypotension and sedation that can be extreme. Psychological treatment and training for behavioral changes is an adjunct therapy commonly used with medications. In order to alleviate opioid poisoning and withdrawal symptoms, a treatment with more desirable side effects is needed.

Ethanol is the most commonly used and abused sedative in most civilized societies, and is a major cause of disease and death. Repeated ingestion of large amounts of ethanol can adversely affect virtually all organ systems of the body, especially the gastrointestinal tract, cardiovascular, and central and peripheral nervous systems. Gastrointestinal effects include gastritis, gastric ulcer, duodenal ulcer, cirrhosis, and pancreatitis. Also, the incidence of cancer of the esophagus, stomach, and other parts of the gastrointestinal tract is increased. Cardiovascular effects include a significant increase in hypertension, cardiomyopathy and other muscle diseases, triglycerides and low density lipoprotein cholesterol levels. These cardiovascular effects cause a significant increase in the risk of developing heart disease. Peripheral neuropathy, as evidenced by muscle weakness, and peripheral sensory depression, may also be present. Central nervous system effects include ethanol-induced forgetfulness, which significantly impairs cognitive deficits, severe memory impairment of the cerebellum, degenerative changes, and the ability to encrypt new memories. These effects are generally associated with vitamin deficiency, particularly vitamin B deficiency.

People with ethanol dependence or addiction are more likely to have a history of dyspepsia, nausea, bloating, esophageal varices, hemorrhoids, progression, abnormal gait, insomnia, erectile dysfunction, decreased testicular size, feminization associated with a decrease in testosterone levels, Symptoms and physical changes included. Symptoms associated with withdrawal of ethanol include nausea, vomiting, gastritis, mouth dryness, swollen and blistering complexion, and peripheral edema.

A generally accepted treatment for ethanol intoxication and withdrawal is achieved by administering a weaker constant temperature agent such as chloridase. In addition, vitamins, especially vitamin B, are generally administered. Also optionally magnesium sulfate and / or glucose may be administered. Nausea, vomiting and diarrhea are treated symptomatically at the discretion of the physician in charge. Also, disulfiram can be administered to help keep it going. When ethanol is consumed, disulfiram accumulates on the surface of the disulfiram, causing zone and hypotension. To alleviate ethanol poisoning and withdrawal, a treatment with more favorable side effects is needed.

Recently, it has been reported that the abuse of polydragues or combination drugs is increasing at an alarming rate. For example, coagulants and heroin have been commonly abused in drug combinations known as speedballing. The reported increase in abuse results in a synergistic effect that increases the sense of insecurity of the prostitutes.

Thus, there is a need to provide a novel method for alleviating a patient's desire by changing the pharmacological action of an abuse drug in the central nervous system in the treatment of drug abuse. There is also a need to provide new methods for treating combined drug abuse.

The present invention is related to United States Patent Application Serial No. 09 / 209,952, filed December 11, 1998, United States Patent Application Serial No. 09 / 189,166, filed November 9, 1998, and United States Patent Application Serial No. 09 / / 129,253. The above patent applications are incorporated herein by reference.

The present invention is directed to the National Institute of Mental Health (USDAE) under the USDOE / OBER DE-AC02-98 CH10886 contract with the US Department of Energy's Environmental and Energy Research NIMH MH49165) and the National Institute on Drug Abuse (Y1-DA7047-01). Accordingly, the United States government has some rights to the invention.

The present invention relates to the use of irreversible inhibitors of GABA-transaminase for the treatment of substance addiction and for altering the behavior associated with substance abuse. Substance addiction, such as substance abuse, and addiction-related behaviors associated with it, are huge social and economic problems that continue to increase while ruining people.

Figure 1 is a graph showing the rate of change of the volume of distribution (DV) in three groups of cocaine treated animals.

2 is a photograph showing the transaxial parametric DV ratio of the non-human primate brain to the horizontal plane of the body's striatum.

Figures 3a and 3b are graphs illustrating the effect of GVC on motility activity compared to saline-free treatment.

Figure 4 is a graph illustrating the effect of GVG on nicotine induced extracellular dopamine.

Figures 5a and 5b are graphs illustrating the effect of nicotine and GVG on extracellular dopamine levels in the nuclear migrating rats of freely moving mice.

6 is a graph showing the effect of meta-amphetamine on the extracellular dopamine levels of the nuclear Abeben in freely moving rats.

FIG. 7 is a graph showing the effect of GVG on the metam amphetamine-induced changes in the extracellular dopamine levels of the nuclear Abeben in freely moving rats.

Figure 8 is a graph showing the effect of GVG on alcohol induced changes in the extracellular dopamine levels of nuclear aboves of freely moving rats.

Figure 9 is a graph showing the effect of GVG on cocaine, heroin, and cocaine and heroin combinations of extracellular dopamine levels in the nuclear migrating rats of freely moving rats.

SUMMARY OF THE INVENTION The present invention, which has been devised to overcome the conventional necessity, provides a method of treating substance addiction in a mammal (e.g., a primate) suffering from substance abuse by administering to a mammal an effective amount of a pharmaceutical composition or drug comprising gamma-vinyl GABA And provide a way to change behavior related to addiction. The amount of GVG may vary from about 15 gm / kg to about 2 gm / kg, preferably from about 100 mg / kg to about 600 mg / kg, more preferably from about 150 mg / kg to about 300 mg / kg do.

In a preferred embodiment, the invention provides a method of eliminating the nicotine addiction effect by treating a mammal with an effective amount of a composition or medicament comprising GVG. The amount of GVG present in the pharmaceutical composition or drug when treating nicotine addiction is about 15 mg / kg to about 2 g / kg. Preferably the amount is from about 75 mg / kg to about 150 mg / kg, more preferably from about 18 mg / kg to about 20 mg / kg.

In another embodiment, the present invention provides a method of treating addiction-related behavior in a mammal suffering from an addictive drug addiction comprising administering to a mammal an effective amount of GVG or a pharmaceutically acceptable salt thereof Wherein said effective amount is an amount that attenuates the compensating / stimulating effect of an abuse drug selected from the group consisting of a stimulant, an anesthetic analgesic, an alcohol, nicotine, and combinations thereof without changing the compensating / stimulating effect of the mammal's diet .

The amount of GVG is in the range of about 15 mg / kg to about 2 gm / kg, preferably about 15 mg / kg to about 600 mg / kg, more preferably about 150 mg / kg to about 600 mg / kg Change.

According to the present invention there is provided a method of reducing substance addiction and altering addiction-related behavior by using a pharmaceutical composition or drug that is not itself toxic and is highly effective in improving the addiction or addiction related behavior of an addicted patient do. The pharmaceutical composition or medicament that is useful in the methods of the present invention inhibits or eliminates the drug addict's craving for the use of an abuse drug. In addition, elimination of conditions associated with an abuse drug occurs without a hindrance or desire response to GVG. In addition, conditions associated with abuse drug dependence can be reduced or eliminated without altering the motor function of the primate.

In another embodiment, the present invention provides a method of altering the addiction-prone state of a mammal suffering from an addictive drug addiction comprising administering to the mammal an effective amount of GVG or a pharmaceutically acceptable salt thereof Wherein the effective amount is sufficient to alleviate, inhibit or eliminate the condition associated with the craving or use of the abuse drug.

Yet another embodiment of the present invention is a method of altering the addiction-related behavior of a mammal suffering from an addictive drug addiction comprising administering to the mammal an effective amount of a composition or agent that increases the level of GABA in the central nervous system Wherein said effective amount is an amount sufficient to reduce, inhibit or eliminate the behavior associated with the craving or use of an abuse drug.

Another embodiment of the present invention is a method of altering the addiction-related behavior of a mammal suffering from an addiction to an abuse drug combination comprising administering to the mammal an effective amount of GVG or a pharmaceutically acceptable salt, enanthiomer or racemic mixture thereof Wherein said effective amount is an amount capable of reducing, inhibiting or eliminating the behavior associated with the craving and use of said abuse drug combination.

In another embodiment, the invention provides a method of preventing abuse drug addiction comprising administering to a mammal an effective amount of GVG, or a pharmaceutically acceptable salt, enanthiomer, or racemic mixture thereof do.

The present invention provides a highly efficient method for treating substance addiction in a substance addicted mammal, for example a primate, and for altering addiction-related behavior.

As used herein, the term addiction-related behavior refers to a condition resulting from the use of an obsessive material and is characterized by its apparent overall dependence on the substance. The indication of this condition is that (i) the drug is irresistible, (ii) the supply of the drug is stationary, and (iii) there is a high likelihood of recurrence after withdrawal.

For example, cocaine rats experience three levels of drug effects. As a first step, anxiety is reduced, an acute acute binge that is characterized by increased self-esteem and libido, and accidents caused by sexual indiscretion, irresponsible expenditure and reckless behavior. In the second phase (crash), the sense of openness changes into anxiety, fatigue, irritability, and depression. During this period, some habitual men commit suicide. Finally, the third stage (anhedonia) is the time to use the cocaine with limited ability to normalize and longing for the cocaine intoxication effect. References [Gawin and Kleber, Medical Management of Cocaine Withdrawl, 6-8 (ATP Foundation)]. Attachment-related behaviors associated with cocaine habits include conditions associated with drug effects of all three stages.

Abuse medication

Abusive drugs include stimulants, narcotic analgesics, addictive alkaloids such as alcohol and nicotine, or combinations thereof. Examples of stimulants include amphetamine, dextroamphetamine, methamphetamine, penmetrazine, diethylpropion, methylphenidate, cocaine, and pharmaceutically acceptable salts thereof.

Examples of narcotic analgesics include, but are not limited to, alpethanil, alpha-proidine, anileriidin, badtramide, codeine, dihydrocodeine, diphenoxylate, ethylmorphine, levomethorphan, levorphanol, metazocine, , Morphine, opium extract, egg white extract, powdery opium, particulate opium, opium tincture, opium tincture, oxycodone, oxymorphone, petidine, phenazocine, racehemorphan, racemorphan, There are pharmaceutically acceptable salts.

Also, abuse drugs include CNS inhibitors such as barbiturates, chlordiazoxide, and alcohols such as ethanol, methanol and isopropyl alcohol.

The methods of the present invention can be used to treat mammals that are addicted to combinations of abuse drugs. For example, where the mammal can be poisoned by ethanol and cocaine, the present invention is particularly suitable for varying the addiction-related state of a mammal by administering an effective amount of GVG to the mammal.

As used herein, combinations of abuse drugs include combinations of stimulants, narcotic analgesics, and addictive alkaloids, as described above. For example, combinations of abuse medicines include cocaine, nicotine, meta amphetamine, ethanol, morphine, and heroin. The most abundant combinations are cocaine and heroin.

Synergism is observed when a combination of abuse drugs is used. For example, a synergistic increase in cerebral dopamine levels is observed when administered directly to rodents, a direct dopamine release agent, heroin and a dopamine reuptake inhibitor, cocaine. Synergism can be confirmed, for example, by an increase in cerebral dopamine levels at a higher level than would be expected if only one drug was used. Preferably, when using a combination of cocaine and heroin, the synergism is evidenced by an increase in cerebral NAc dopamine levels from about 500% to about 1000% compared to administration of only one drug.

The use of compulsive drugs involves three independent factors: resistance, psychological dependence, and physical dependence. Due to tolerance, it is necessary to increase the dose of the drug after several administrations in order to achieve the same effect. Physical dependence is an adaptive state that is caused by repeated drug administration, which is a state of strong physical impairment when drug administration is discontinued. Psychological dependence is characterized by strong impulses, craving, and use of drugs. References [Feldma, R.S. And Quenzer, L. F., " Fundamentals of Neuropsychopharmocology " 418-422 (Sinaur Associate, Inc.), 1984). As used herein, the term " dependency " as used herein includes all characteristics associated with the use of an obsessive drug, and features that may be influenced by the biochemical composition, physical and psychological characteristics of the recipient.

As described above, when an obsession drug or an abuse drug combination is used, a craving step of the taking effect of the drug occurs after the taking step, and the drug is used. As used herein, the term " compensating / stimulating effect " of an abuse drug means any stimulant that increases the likelihood of a learned response. This term is synonymous with enhancement. In experimental animals, irritants are judged to be compensated using a paradigm that measures compensation. This reward can be achieved by measuring whether the stimulus causes an approaching response, also known as a desire response, or whether the animal experiences a withdrawal, also known as an avoidance response, when it avoids stimulation. A conditioned place preference (CPP) is a paradigm that measures desire (access response) or withdrawal response (avoidance). Reward stimulation can assume that access behavior occurs. Also, as a result of the compensation, the stimulation characteristics associated with compensation can be increased.

It is also possible to measure compensation by determining whether the transfer of compensation is accompanied by a particular response so that the response can increase the likelihood of reoccurrence in a particular situation. For example, a mouse that pushes a bar a certain number of times during the injection of cocaine is an example of enhancement. Another way to measure reward is to measure whether a stimulant (eg, a drug) leads to the previous neutral environmental stimuli to elicit behavioral effects that are only associated with the drug initially, through multiple matings with neutral environmental stimuli . CPP is considered to be a form of harmonization.

The stimulation value of a drug or other stimulant can be assessed using a conditioning site selection (CPP). In the absence of drugs, the animals are tested in the absence of drugs in cocaine, nicotine, heroin, morphine, meta amphetamine, ethanol or other abuse drugs or combinations thereof to determine if the animals are environmentally acceptable Or not. In the CPP paradigm, animals in one separate environment are provided with drugs and animals in other environments are provided with appropriate excipients. The CPP paradigm is widely used to evaluate the stimulating effect of drugs in experimental animals (Van Der Kooy, 1995). After conditioning and mating with the drug, if the animal in a drug-free state chooses an environment that is consistent with the abuse drug, the abuse drug's desire value is coded in the brain and accessible It can be concluded. CPP is reflected in an increase in the time spent in the presence of drug-related stimuli as compared to the untreated animals injected with the vehicle. CPP can also be used to assess the addiction to a combination of abusable drugs.

Since human cravings are often derived from sensory stimuli already associated with drug ingestion, a conditioning paradigm such as CPP can be used to sample the cravings of laboratory animals.

As used herein, the aspiration of a combination of desiring or abusing drugs of an abuse drug is a strong desire to self-administer a drug already used by a mammal. Mammals do not require abuse medications to prevent withdrawal.

The addiction of abuse drugs such as cocaine, nicotine, methaamphetamine, morphine, heroin, ethanol or other abuse drugs has led to the pharmacological action of the central nervous system (CNS) on the mesothecaemal dopamine (DA) enrichment / compensation pathway. Within this pathway, the delivery of dopamine-like drugs is regulated by gamma aminobutyric acid (GABA).

For example, cocaine, nicotine, meta- amphetamine, heroin, and ethanol suppress synaptic reabsorption of monoamines. The dopaminergic neurons of the mesocorticolimb DA system, which have cell bodies in the intrave- nous sheath zone (VTA) and extend to the nucleus albinum (NACC), are thought to be involved in cocaine, nicotine, meta- amphetamine, morphine, heroin or ethanol enrichment . Electrical stimulation of the compensatory center within the VTA abolishes self-administration of cocaine, nicotine, meta- amphetamine, morphine, heroin or ethanol, as the extracellular DA levels of the NACC increase with the 6-hydroxydopamine pathway of the NACC. In vivo microdialysis studies have demonstrated the ability of cocaine, nicotine, methamphetamine, morphine, heroin and ethanol to increase the extracellular DA of NACC.

The gamma-aminobutyric acid (GABA) neurons of NACC and abdominal Palladium are projected onto the DA neuron of VTA. Pharmacological and electrophysiological studies have shown that the above projections are inhibited. Inhibition of VTA-DA neurons may result in stimulation of GABA _B receptors. In addition, microinjection of vaclofen into VTA while acting through the subtypes of the receptors may reduce the DA concentration of NACC. Pharmacological manipulation of GABA may affect the DA level of NACC through modulation of VTA-DA neurons.

Gamma vinyl GABA

Gamma-Vinyl GABA (GVG) is a selective and irreversible inhibitor of GABA-transaminase (GABA-T), which is known to increase GABA inhibition. In addition, GABA changes the biochemical action of cocaine by causing a dose-dependent long-term increase in extracellular endogenous brain GABA levels.

GVG is C ₆ H ₁₁ NO ₂ or 4-amino-5-hexanoic acid available under the trade name Vigabatrin from Hoechst Marion Roussel, available from Marion Merel Dow, Cincinnati, Ohio, USA. GVG does not bind to any receptor or reabsorption complex but increases GABA levels in endogenous cells by selectively and irreversibly inhibiting GABA-transaminase (GABA-T), an enzyme that normally transactivates GABA.

GVG as used herein includes racemic compounds or mixtures containing the same amounts of S (+) - gamma-vinyl GABA and R (-) gamma-vinyl GABA. Such racemic mixtures of GVG are available from Hoechst Marion Roussel under the trade designation Vigabatrin and from Marion Merell Dow, Cincinnati, Ohio, USA.

The GVG contains an asymmetric carbon atom and thus can exist in an enantiomeric form. The present invention encompasses any enantiomeric form of GVG, including racemic or racemic mixtures of GVG. In some cases, the use of a particular enantiomer may be advantageous, i.e. better efficacious, than using other enantiomers or racemates or racemic mixtures, Can be easily determined.

For example, the enantiomer S (+) - gamma-vinyl GABA is more effective than the enantiomer R (-) - gamma-vinyl GABA in increasing endogenous GABA levels.

The different enantiomers can be synthesized from different asymmetric chelates, or the racemates can be dissolved using conventional procedures well known in the chemical arts such as chiral chromatography, fractional crystallization of diastereomeric salts, and the like .

Administration of gamma-vinyl GABA

In a live mammal (in vivo), GVG or a pharmaceutically acceptable salt thereof can be administered systemically via the parenteral and enteral routes, which also include a controlled release delivery system. For example, GVG may be administered via the intraperitoneal route (i.p.) or the intravenous route, which is the preferred delivery route. Such intravenous or intraperitoneal administration can be accomplished by mixing GVG with a suitable pharmaceutical carrier or excipient known to those skilled in the art.

Oral or intestinal use may be envisaged, and preparations such as tablets, capsules, pills, pills, elixirs, suspensions, syrups, wafers, chewing gums and the like may be used to provide GVG or a pharmaceutically acceptable salt thereof.

As used herein, pharmaceutically acceptable salts include salt-forming acids and bases which do not substantially increase the toxicity of the compounds. Examples of suitable salts include salts of inorganic acids such as hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and salts of sulfuric acid, and organic acids such as tartaric acid, acetic acid, maleic acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, , p-toluenesulfonic acid), and the like.

As used herein, an effective amount refers to an amount effective to achieve the above-described effect of changing the addiction-related behavior of a mammal. E., An amount that alleviates or reduces one or more symptoms or conditions resulting from the withdrawal or withdrawal of a stimulant, narcotic analgesic, alcohol, nicotine, or combination thereof. However, it goes without saying that the present invention is not limited to any specific dosage.

It is preferred that the GVG is administered in an amount that has almost no side effects. For example, the dosage is about 15 mg / kg to about 2 g / kg, or about 15 mg / kg to about 600 mg / kg.

For example, to treat cocaine poisoning, the GVG may be administered at a dose of about 15 mg / kg to about 2 g / kg, preferably about 100 mg / kg to about 300 mg / kg or about 15 mg / kg to about 600 mg / kg, more preferably from about 150 mg / kg to about 300 mg / kg, or from about 75 mg / kg to about 150 mg / kg.

For example, to treat nicotine addiction, GVG may be administered at a dose of about 15 mg / kg to about 2 g / kg, or about 15 mg / kg to about 600 mg / kg, preferably about 100 mg / kg to about 300 mg / kg or from about 150 mg / kg to about 300 mg / kg, more preferably from about 18 mg / kg to about 20 mg / kg to about 75 mg / kg to about 150 mg / kg.

For example, to treat meta- amphetamine poisoning, the GVG may be administered at a dose of about 15 mg / kg to about 2 g / kg, preferably about 100 mg / kg to about 300 mg / kg, or about 15 mg / kg to about 600 mg / kg, more preferably from about 150 mg / kg to about 300 mg / kg, or from about 75 mg / kg to about 150 mg / kg.

When the mammal is poisoned with a combination of abuse medicines, such as, for example, cocaine and heroin, the GVG is from about 15 mg / kg to about 2 g / kg, preferably from about 100 mg / kg to about 300 mg / kg or Is administered to the mammal in an amount of about 15 mg / kg to about 600 mg / kg, more preferably about 150 mg / kg to about 300 mg / kg or about 75 mg / kg to about 150 mg / kg.

In addition to humans, baboons and other primates, examples of mammals include pets such as dogs and cats, laboratory animals such as mice and mice, and livestock such as horses, sheep and cows.

Gamma-Vinyl GABA (GVG) is a selective and irreversible inhibitor of GABA-transaminase (GABA-T), which is known to enhance GABA inhibition. It is also known that GVG alters the biochemical effect of cocaine by causing a dose-dependent and long-term increase in extracellular endogenous brain GABA levels.

Based on the theory that other abusive drugs in addition to cocaine increase the extracellular NACC DA and that GABA inhibits DA in the same nucleus, GVG weakens cocaine, nicotine, methamphetamine, and ethanol-induced changes in extracellular DA Respectively. As an example, acute (single injection) and chronic (11 days) GVG administration effects on cocaine-induced changes in extracellular DA concentrations of NACC were confirmed using freely moving animals using microdialysis. References [Morgan, A.E. Et al., &Quot; Effect of Pharmacologic Increases in Brain ABA Levels on Cocaine-Induced Changes in Extracellular Dopamine ", Synapse 28: 60-65 (1998). All disclosures of the above references are incorporated herein by reference.

Unexpectedly, inhaling GVG confirmed that the addictive state associated with biochemical changes resulting from inhalation of the abusive drug changes. For example, GVG attenuates the cocaine-induced increase in synaptic dysplasia of primate (BB) brains as confirmed by positron emission tomography (PET) and abolishes the expression or acquisition of cocaine- do. However, GVG did not affect the delivery of cocaine for food compensation or cocaine for brain exercise. From these confirmations, it can be seen that the pharmacological method used for the treatment of cocaine poisoning is targeting the GABA neurotransmitter system, which is operatively linked to the system, although it is separated from the DA mesothecaemal compensatory / enhancer system. However, rather than targeting a GABA receptor complex using a direct GABA agonist, the new method of using GVG has the effect of an irreversible enzyme inhibitor that increases endogenous GABA levels without addictivity associated with GABA agonists directly acting on the receptor itself It has the advantage of lasting over a long period of time.

Although GVG is used in embodiments of the present invention, those skilled in the art will appreciate that other compositions or agents known to enhance the GABA system or increase the extracellular endogenous GABA levels of the CNS may be used.

Such compositions or medicaments include drugs that enhance the production or release of GABA in the CNS. Examples of such drugs include, but are not limited to, gabapentin, valproic acid, progabide, gamma-hydroxybutyric acid, fenugin, cetyl GABA, topiramate, thiabbin, Lt; RTI ID = 0.0 > enantiomeric < / RTI > or racemic mixtures.

The present invention relates to the use of racemic or racemic or racemic forms, including any enantiomeric forms of gabapentin, valproic acid, progabide, gamma-hydroxybutyric acid, fenugin, cetyl GABA, topiramate, thiabbin, And mixtures thereof.

As noted above, in some cases it may be advantageous to use certain enantiomers compared to using other enantiomers or racemates or racemic mixtures of the process of the present invention, Which may be easily determined by those skilled in the art.

The present invention includes compositions or medicaments comprising a prodrug of GABA or a drug that partially contains GABA in its chemical structure. Such prodrugs exhibit pharmacological activity when metabolized, degraded enzymatically or nonenzymatically to GABA in the CNS. An example of a prodrug of GABA is progababide, which increases endogenous CNS GABA levels across the blood-brain barrier.

As described above, gamma-vinyl GABA (GVG) is a selective and irreversible inhibitor of GABA-transaminase (GABA-T) which is known to enhance GABA inhibition. Also included in the present invention are other compositions or agents that inhibit GABA reabsorption of the CNS. An example of a GABA reuptake inhibitor is thiabergine.

The methods of the present invention are useful in enhancing the GABA system or increasing the extracellular endogenous GABA levels of the CNS. As used herein, enhancing or increasing endogenous CNS GABA levels is defined as the actual increase or upregulation of mammalian GABA levels above normal levels. Preferably the endogenous CNS GABA level is improved by at least about 10% to about 600% above the normal level.

As noted above, an effective amount as used herein means an amount effective to achieve the above-described effect of changing the addiction-related state of a mammal. This amount is an amount that can alleviate or reduce one or more conditions or symptoms resulting from the interruption or withdrawal of the stimulant, narcotic analgesic, alcohol, nicotine, or combination thereof. However, it goes without saying that the present invention is not limited to any specific dosage.

For example, an effective amount of gabapentin administered to a mammal is about 500 mg to about 2 g / day. Gabapentin is available as Neurontin ^™ from Parke-Davis, USA.

For example, an effective amount of valproic acid to be administered to a mammal is preferably from about 5 mg / kg to about 100 mg / kg per day. Valproic acid is available as Depakene ^TM from Abbott of the United States of America.

For example, an effective amount of topiramate administered to a mammal is preferably from about 50 mg to about 1 g per day. Topiramate is available as a possible Topamax ^TM from McNeil in the United States. The effective amount of pro-isobide to be administered to the mammal is preferably from about 250 mg to about 2 g per day. Progabid is available as Gabrene ^TM from Synthelabo, France. The chemical formula of the bead profile is a _{C 17 H 16 N 2 O 2} .

The effective amount of pengervin administered to the mammal is preferably from about 250 mg to about 4 g per day. Pen Gavin is available as SL 79229 from Synthelabo, France. Pen Gavin formula is C ₁₇ H ₁₇ C ₁₂ NO.

The effective amount of gamma hydroxybutyric acid administered to the mammal is preferably from about 5 mg / kg to about 100 mg / kg per day. Gamma-hydroxybutyric acid is available from Sigma Chemical. The formula for gamma-hydroxybutyric acid is C ₄ H ₇ O ₃ Na.

The improvements obtained by the present invention can be ascertained through the following detailed description that describes preferred embodiments of the present invention. The following description is not intended to limit the scope of the invention, but merely to provide a preferred embodiment of the invention. The scope of the present invention will be described in the claims.

The invention is further illustrated by reference to the following examples. The scope of the invention is set forth in the claims.

Example

The following examples are intended to illustrate the best mode of carrying out the invention for illustration. The scope of the present invention is not limited to the following examples.

Materials and methods

1. PET studies of primates

In all studies, 20 adult mature female baboons (Papio anubis, 13-18 kg) were used and carbon-11 labeled lacrolprides previously identified as sensitive to changes in synapse DA were synthesized as previously described Volkow et al., 1994). Arterial blood samples were obtained during the study and selected plasma samples were analyzed for the presence of non-altered radioactivity tracing carbon-11. The animals were removed from the gantry after each injection of the isotope. Critical areas (ROIs) were drawn on PET images. Briefly, whenever the striatum appears, it is drawn in both directions on a transaxial slice. The cerebellar ROI was drawn across the centerline at the height of the cerebellum. Next, the ROI obtained from the first study was copied directly on the corresponding slice obtained from the second study. If necessary, only the position of the ROI can be changed by checking the position of the ROI on the second scan. Using this multi-plane analysis method, we have reduced the differences that can occur due to the movement of animals within the gantry during the injection interval.

The schematic method for determining the distribution volume (DV) has already been developed for the kinetic analysis of [ ¹¹ C] -lactopreide data. The DV ratio is the most reproducible measure of the absorption of lacronpride. This ratio is the ratio of DV liberated from the receptor-rich region (striatum) to DV in the non-receptor region (cerebellum). The free receptor concentration is directly proportional to the DV ratio of 1. Animals were prepared as previously described (Dewey et al., 1992).

The statistical analysis was to test the hypothesis that (1) the cocaine challenge is different from the test / retest variability (carried out on the same animal under the same experimental conditions) of radioactively traced carbon-11 and (2) the conduction conditions are different from each other. From the fact that the ratio of striatum and striatum to cerebellum is important but not for the cerebellum, it is found that the intervention effect is limited to specific binding factors, not nonspecific binding factors. GVG not only did not change the area distribution of the radioactive tracer but also did not change the metabolic rate.

2. Cocaine-Induction Conditioning Site Selection

For all animal studies, male Sprague-Dawley rats (200-225 g, Taconic farms in Germantown, New York, USA) were used. The animals were acclimated to animal accommodation for at least 5 days prior to beginning the experiment. The inventors of the present invention used a conditioning site selection (CPP) chamber as previously described (Lepore et al., 1995). However, in the prior art, one chamber is completely white and the other chamber is black, In the case of the invention, one chamber was a light blue with a stainless steel floor and the second chamber was a light blue with horizontal black strips (2.5 cm wide) spaced 3.8 cm apart with a flat plexiglass floor. For all CCP studies using GVG, the saline volume was 1 ml / kg and the cocaine dose was 20 mg / kg. The saline, cocaine and GVG were injected into the peritoneum. The conditioning step for the acquisition phase consisted of 12 consecutive sessions over 12 days.

The CPP matings were 1) saline / brine, 2) saline / cocaine, 3) GVG / brine, 4) saline / cocaine and GVG. Each group of animals was randomly assigned with a 2 x 2 factoring scheme, one factor being the mating chamber and the other factor being the degree of conditioning. Animals receiving saline or cocaine were confined in a suitable compartment for 30 minutes. GVG injections were performed 3 hours before the animal was placed in the appropriate chamber by injecting saline or cocaine into the animal. This GVG injection was proven to reach a maximum level of GABA at 3 to 4 hours after GVG administration.

During the test period (12 days) no drug or saline was administered and the animals were allowed to move freely between the two chambers. The time spent in each chamber was recorded using an automatic infrared beam that was electronically coupled to the timer. During the expression phase of CPP for cocaine, the animals were accustomed to cocaine as described in the acquisition study, but the animals in the expression step did not provide GVG during conditioning. During the test period (12 days), the animals tested in the expression step, unlike the animals tested in the obtaining step, were placed in the apparatus when 2.5 hours had passed after the saline or GVG was provided and the two chambers were freely accessible for 15 minutes Respectively.

3. Food-induced conditioning of selected animal

To test the food-induced CPP of the rodents, four groups of animals were randomly accessed during the CPP process of the 12 sessions. The CPP process of session 12 was the same as that used in the cocaine-induced CPP study except that the desensitizer material was a non-cocaine food. Prior to CPP mating on one side of the CPP box by exposure to food, saline was given to the first group, intra-peritoneal injection of 150 mg / kg GVG to the second group, saline administration to the third group, Group 4 received intraperitoneal injection of 300 mg / kg of GVG. The four groups of animals were accustomed to the Froot Loops located in the appropriate chambers of the experiment room during the four taming sessions, which is an interesting fruit flavor breakfast cereal. After 24 hours after the final CPP mating, the animals were placed in the chamber and did not receive drug or saline. The animals were also allowed to move freely within the CPP apparatus for 15 minutes. The time spent in the paired chambers and unpaired chambers was recorded using an automated instrument.

4. Measured athletic activity of rodents

Prior to the experiment, the animals were pre-treated for 5 minutes daily for a week to reduce handling stress. During the study period, GVG (150 mg / kg or 300 mg / kg) or saline (1 ml / kg or 0.5 ml / kg) was intraperitoneally administered 2.5 hours before the experiment. One hour before the experiment, the animals were transported to the test site. 2.5 hours after administration of GVG or saline, the animals were placed in the behavior cage and the activity data were recorded on a PC-AT computer using the Photobeam Activity Systemd for 90 minutes at 10 minute intervals. The exercise cage is a 41.3 x 41.3 x 30.5 cm transparent acrylic cage. An electronic device (the Photobeam Activity System, available from San Diego Instruments, San Diego, Calif., USA) used to measure the motility activity includes 16 infrared beams projected from left to right across the cage, And 16 beams. All infrared beams are about 0.39 cm from the floors.

5. Studies on the hardness of rodents

After intraperitoneal administration of 150 mg / kg GVG, 300 mg / kg GVG or saline (1 ml / kg, i.p., 0.9% saline), the degree of hardening was measured using a bar test. Briefly, male Sprague-Dawley rats were handled and transported to the lab 3 days before the experiment to make them compliant. At the time of testing, 10 animals per treatment group were given saline or GVG, and the degree of hardening was measured at 60, 120 and 240 minutes after challenge. Experiments were prevented from seeing the treatment given to each animal. The bar was made of wood and had a diameter of 1.2 cm, and the height from the floor to the top of the bar was 10 cm. For each measurement, the paws of the animals were placed on the bar and the time taken for the animals to transfer their paws to the flue was measured.

6. Animal and primate [ ¹¹ C] - Cocaine study

Ten animals were divided into two groups. Group 1 received peritoneal administration of saline (1 ml / kg) 3 hours prior to administration of [ ¹¹ C] -cocaine. Group 2 received intraperitoneal administration of GVG (300 mg / kg) three hours before [ ¹¹ C] -cocaine. The animals were killed 10 minutes after administration of [< ¹¹ > C] -cocaine. The brain was removed and the radioactivity was measured. In two additional primate PET studies, GVG (300 mg / kg) was administered immediately after baseline scan using labeled cocaine. Approximately 3 hours later, the animals were reinitiated with the labeled cocaine and injected for 60 minutes.

7. Studies on microdialysis of rodents

All animals were used in accordance with the IACUC Approvals Code, strictly following the NIH guidelines. 12: 12 Mature male Spraque-Dawley rats (200-300 g, Taconic Farms) housed in animal housing under light / dark conditions were anesthetized by dividing into six groups (n = 5-9) , The siliconeization guide cannula was implanted stereotaxically within the right NACC (2.0 mm forward, 1.0 mm lateral, and 7.0 mm from the cortical surface). Traces of the dialysis probes (2.0 mm, BAS, Bioanalytical Systems U.S. indicator energy state, based in West Lafayette BAS) was placed inside the guide cannula artificial cerebrospinal fluid ^{(ACSF, 155.0 mM NA -,} 1.1mM Ca 2-, 2.9 mMK -, 132.76 mM Cl-, and 0.83 mM Mg ^2- ) were administered via a CMA / 100 microinjection pump (BAS) at a flow rate of 2.0 l / min. Animals were placed in a bowl, probes were inserted and flushed overnight using ACSF. During the study, baseline stability was measured by minimally injecting three samples. Samples were collected for 20 minutes and injected online (CMA / 160, BAS). The mean dopamine concentration of these three stable samples was set as the countermeasure (100%) and all subsequent treatments were converted to% of the above measures. When setting a stable baseline, nicotine was administered by intravenous injection. High Performance Liquid Chromatography (HPLC) systems include a BAS reversed phase column (3.0 μC-18), a BAS LC-4C electrochemical transducer with a 650 mV double / glassy carbon electrode, a computer that analyzes data on-line using a commercial software package (Chromograph Bioanalytical Systems), and a dual pen chart recorder. The mobile phase (flow rate 1.0 ml / min) consists of 7.0% methanol, 50 mM monobasic sodium phosphate, 1.0 mM sodium octyl sulfate, and 0.1 mM EDNA. DA was eluted at 7.5 min. At the end of the study, animals were killed and frozen for confirmation of probe placement.

In parallel with quantitative assessment of dopamine concentration, the animal's motor response to administration of stimulants was quantified using an infrared motion sensor. This infrared optical proximity detector measures the movement of the horizontal holding arm (integral element of the free moving device). The digital output of the detector was connected to a IBM personal computer and programmed to calculate the positive and negative bias. These data were collected and totaled using the same sampling method as used for the dialysis sample. The kinetic activity was then expressed as the number of deflections per sample interval.

Example 1

Studies of primates (Bibi) except man

20 primates were injected twice with [ ¹¹ C] -lacurfide according to the procedure described in Section 1 of Materials and Methods above. The first injection was used as the baseline and the second injection thereafter was cocaine or placebo. Test / retest primates (n = 7) identified as the first group in Table 1 below were injected with placebo (0.9% saline, 1 ml / kg) Variability was measured.

Group and experiment conditions group Drug condition One Control group 2 Cocaine treatment 3 GVG / cocaine treatment

All remaining primates (n = 13) were injected with cocaine hydrochloride (0.5, 1.0 or 2.0 mg / kg) 5 minutes or 30 minutes prior to the injection of the second [ ¹¹ C] -lactopride. Among these 13 animals, 5 were injected with GVG (300 mg / kg) 3 hours before cocaine administration.

Even when the cocaine dose and the cocaine pretreatment time interval were made different, the effect of cocaine on the distribution volume (DV) did not change much as expected. Thus, the mean% change in DV ratio between animals treated with cocaine alone (n = 8) and animals treated with GVC / cocaine (n = 5) are as shown in Groups 2 and 3, respectively,

The binding of [&lt; ¹¹ &gt; C] -lactrofuride as a competitive antagonist depends on the DA concentration of the synaptic cleft. That is, as the synaptic DA concentration decreases, [ ¹¹ C] -lactopride binding also decreases. As shown in Figure 1, the test / retest variability of this imaging method was less than 7% for group 1. The variability of these PET measurements is consistent with the previous values obtained using [ ¹¹ C] -lactopride for primates. In group 2, cocaine reduced the mean DV ratio (p <0.0002, Student's two tailed t-test, Figure 1) by more than 30%. These data were consistent with a concurrent study of PET and micronutrient dialysis. In this concurrent study, amphetamines increased the extracellular DA of the primate brain and reduced [ ¹¹ C] - lacrolide binding. In addition, this confirmation is similar to recent reports showing the effect of cocaine on labeling coclopride binding in humans. Finally, the data show that the inventors' studies using microdialysis studies of our inventors (Morgan and Dewey, 1998) and amphetamines, GBR 12909, tetrabenzazin, methylphenidate and [ ¹¹ C] , 1993; Volkow et al., 1994). However, pretreatment with GVG significantly inhibited the cocaine-induced decrease in DV ratio (p &lt; 0.002, Student's two tailed t-test) as shown in group 2 of FIG. This difference can be easily seen from the parametric DV non-image as shown in Fig. Values for groups 1 and 3 were not statistically different (p <0.002, Student's two-tailed t-test).

Example 2

Study on selection of conditioning site by cocaine in rodents

In this example, the procedure described in the Materials and Methods section 2 was used. Cocaine causes a dose-dependent CPP response, which occurs when the most reliable and firm response is 20 mg / kg as shown in Table 2 below.

Select Conditional Place for Cocaine Cocaine (mg / kg) Time spent in chamber (min) Mated chamber Unmated Chamber ¹ 0 7.4 ± 0.3 7.6 ± 0.3 5.0 8.2 ± 0.4 6.8 ± 0.5 10.0 9.6 ± 0.5 ² 5.4 ± 0.3 20.0 11.8 ± 0.4 ³ 3.2 ± 0.4 ⁴

¹ Test animals were injected with saline only

Significantly higher than cocaine at ² 0 and 5 mg / kg doses, p &lt; 0.05, ANOVA and Student-Newman-Keuls test.

³ significantly higher than cocaine at 0.5 and 10 mg / kg doses, p &lt; 0.05, ANOVA and Student-Newman-Keuls test.

⁴ significantly higher than cocaine at 0.5 and 10 mg / kg doses, p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

Therefore, the inventors of the present invention investigated the effect of GVG on the step of obtaining and expressing cocaine-induced CPP by selecting a dose of 20 mg / kg of cocaine. As a result, GVG at doses of 112, 150, and 300 mg / kg inhibited the acquisition and expression of cocaine-induced CPP, rather than the dose of 75 mg / kg. See Table 3-10 below.

Effects of GVG and salt water on cocaine-induced conditioning site selection Treatment mating ¹ Time to send from chamber (minutes) Mated chamber Unpaired chamber ² Brine / brine 7.3 ± 0.5 7.7 ± 0.6 Saltwater / cocaine 11.1 ± 0.3 ⁴ 3.9 ± 0.4 75 mg / kg GVG ³ / brine 7.3 ± 0.5 7.7 ± 0.6 75 mg / kg GVG ³ / cocaine 9.1 ± 1.1 5.9 ± 1.2

¹ Each value represents the mean value of the time spent in each chamber ± SSM (n-8-10).

² Only animals were injected with salt water.

Animals were given GVG or saline 2.5 hours prior to the administration of ^tri- saline or cocaine (20 mg / kg).

⁴ Significantly higher than all treatment groups. p &lt; 0.05, ANOVA and Student-Newman-Keuls test.

⁵ Significantly lower than all treatment groups. p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

Mating treatment ¹ Time to send from chamber (minutes) Mated chamber Unpaired chamber ² Brine / brine 7.2 ± 0.5 7.8 ± 0.4 Saltwater / cocaine 11.8 ± 0.5 ⁴ 3.2 ± 0.5 112 mg / kg GVG ³ / brine 7.6 ± 0.6 7.4 ± 0.6 75 mg / kg GVG ³ / cocaine 8.2 ± 0.5 6.8 ± 0.5

¹ Each value represents the mean ± SSM (n-8-10) of the time spent in each chamber.

² Only animals were injected with salt water.

Animals were given GVG or saline 2.5 hours prior to the administration of ^tri- saline or cocaine (20 mg / kg).

⁴ Significantly higher than all treatment groups. p &lt; 0.05, ANOVA and Student-Newman-Keuls test.

⁵ Significantly lower than all treatment groups. p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

Mating treatment ¹ Time to send from chamber (minutes) Mated chamber Unpaired chamber ² Brine / brine 7.4 ± 0.3 7.6 ± 0.4 Saltwater / cocaine 11.6 ± 0.5 ⁴ 3.4 ± 0.4 ⁵ 150 mg / kg GVG ³ / brine 7.6 ± 0.6 7.2 ± 0.6 150 mg / kg GVG ³ / cocaine 7.9 ± 0.8 7.1 ± 0.8

¹ Each value represents the mean ± SSM (n-8-10) of the time spent in each chamber.

² Only animals were injected with salt water.

Animals were given GVG or saline 2.5 hours prior to the administration of ^tri- saline or cocaine (20 mg / kg).

⁴ Significantly higher than all treatment groups. p &lt; 0.05, ANOVA and Student-Newman-Keuls test.

⁵ Significantly lower than all treatment groups. p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

Mating treatment ¹ Time to send from chamber (minutes) Mated chamber Unpaired chamber ² Brine / brine 7.7 ± 0.3 7.3 ± 0.3 Saltwater / cocaine 11.2 ± 0.6 ⁴ .8 ± 0.5 ⁵ 300 mg / kg GVG ³ / brine 7.2 ± 0.4 7.8 ± 0.4 300 mg / kg GVG ³ / cocaine 7.6 ± 0.7 7.2 ± 0.7

¹ Each value represents the mean value of the time spent in each chamber ± SSM (n-8-10).

² Only animals were injected with salt water.

Animals were given GVG or saline 2.5 hours prior to the administration of ^tri- saline or cocaine (20 mg / kg).

⁴ Significantly higher than all treatment groups. p &lt; 0.05, ANOVA and Student-Newman-Keuls test.

⁵ Significantly lower than all treatment groups. p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

Effects of GVG and salt water on the expression of cocaine-induced conditional site selection Treatment mating ¹ Drugs to be administered at the time of testing Time to send from chamber (minutes) Mated chamber Unpaired chamber ² Brine / brine Brine 7.5 ± 0.4 ¹ 7.5 ± 0.4 Brine / brine GVG, 75 mg / kg 7.5 ± 0.3 7.5 ± 0.3 Saltwater / cocaine Brine 11.8 ± 0.5 ³ 3.2 ± 0.5 Saltwater / cocaine GVG, 75 mg / kg 10.6 ± 0.6 ³ 4.4 ± 0.9 Brine / brine Brine 7.8 ± 0.5 ¹ 7.2 ± 0.6

¹ Each value represents the mean ± SSM (n = 10) of the time spent in each chamber.

² Only animals were injected with salt water.

³ significantly higher than all other treatment groups. p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

Mating treatment ¹ Drugs to be administered at the time of testing Time spent in chamber (minutes) Mated chamber Unpaired chamber ² Brine / brine Brine 7.1 ± 0.5 7.9 ± 0.5 Brine / brine GVG, 112 mg / kg 7.2 ± 0.3 7.8 ± 0.3 Saltwater / cocaine Brine 12.2 ± 0.6 ³ 2.8 ± 0.5 Saltwater / cocaine GVG, 112 mg / kg 8.1 ± 0.7 6.9 ± 0.6

¹ Each value represents the mean ± SSM (n = 10) of the time spent in each chamber.

² Only animals were injected with salt water.

³ significantly higher than all other treatment groups. p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

Mating treatment ¹ Drugs to be administered at the time of testing Time to send from chamber (minutes) Mated chamber Unpaired chamber ² Brine / brine Brine 7.2 ± 0.2 ¹ 7.8 ± 0.2 Brine / brine GVG, 150 mg / kg 7.7 ± 0.2 7.3 ± 1.1 Saltwater / cocaine Brine 11.1 ± 0.5 ³ 3.9 ± 0.4 ⁴ Saltwater / cocaine GVG, 150 mg / kg 7.9 ± 0.3 7.1 ± 0.3

¹ Each value represents the mean ± SSM (n = 10) of the time spent in each chamber.

² Only animals were injected with salt water.

³ significantly higher than all other treatment groups. p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

⁴ significantly lower than all other treatment groups. p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

Mating treatment ¹ Drugs to be administered at the time of testing Time to send from chamber (minutes) Mated chamber Unpaired chamber ² Brine / brine Brine 7.8 ± 0.5 ¹ 7.2 ± 0.6 Brine / brine GVG, 300 mg / kg 7.3 ± 0.4 7.7 ± 0.3 Saltwater / cocaine Brine 12.5 ± 0.8 ³ 2.5 ± 0.6 ⁴ Saltwater / cocaine GVG, 300 mg / kg 7.9 ± 0.5 7.1 ± 0.6

¹ Each value represents the mean ± SSM (n = 10) of the time spent in each chamber.

² Only animals were injected with salt water.

³ significantly higher than all other treatment groups. p &lt; 0.05, ANOVA and Student-Newman-Keuls test.

⁴ significantly lower than all other treatment groups. p &lt; 0.05, ANOVA and Student-Newman-Keuls test.

The GVG itself caused CPP and conditioning avoidance responses. See Table 3-10 for this.

Example 3

Preference study on food-induced conditioning condition of animal

The procedure described in Section 3 of the above materials and methods was carried out in this implementation. From the results in Table 11 below, it can be seen that the food induces stimulation or compensation effect. For example, from the paired value, it can be seen that the animal remains in the chamber where food is present for a long time.

Effect of GVG (150, 300 mg / kg, ip) on food-induced conditioning site selection Mating treatment agent Time spent in chamber (minutes) Mated chamber Unpaired chamber Brine / brine 7.3 ± 0.6 7.7 ± 0.6 GVG / brine 7.5 ± 0.7 7.5 ± 0.7 Saltwater / food 9.3 ± 0.7 5.7 ± 0.7 GVG (150 mg / kg) / food 9.4 ± 0.4 5.6 ± 0.5 GVG (350 mg / kg) / food 9.0 ± 0.5 6.0 ± 0.5

¹ Each value represents the mean ± SSM of the time spent in each chamber.

² Only animals were injected with salt water.

When 150 or 300 mg / kg of GVG was administered, as shown in the above Table 3-10, although the stimulating effect of cocaine was weakened during the CPP experiment, the CPP response to food was changed It does not.

Examination of experimental results obtained in Examples 1, 2 and 3

In previous PET studies, the inventors of the present invention have found that GVG alone increases [ ¹¹ C] -lactopride binding of primate brains by decreasing extracellular DA concentration (Dewey et al., 1992). In the PET study of the present invention, reducing the extracellular DA levels using GVG prior to administration of cocaine causes the cocaine effect observed in Group 3 of Table 1 to be attenuated. However, from the apparently identical values identified for Groups 1 and 3 with the previous identification of the present inventors using only GVG, it can be seen that cocaine increases the extracellular DA level to baseline despite administration of GVG.

However, based on the CPP data presented herein, the cocaine-induced feedback at baseline is clearly insufficient to produce a stimulating effect. From the results of the present invention, it can be seen that cocaine causes a CPP reaction. By comparison, it can be seen that the conjugation of the excipient does not cause a CPP response, so the animal does not exhibit chamber preference. In addition, the CPP response to cocaine is dose dependent, with the most reliable and firm response occurring when the dose of cocaine is 20 mg / kg.

Administration of 112, 150 and 300 mg / kg of GVG, rather than 75 mg / kg, inhibits the acquisition and expression of cocaine-induced CPP responses. By comparison, when paired with saline, GVG does not cause CPP or repulsion. From these facts, blocking cocaine-induced CPP using GVG is not associated with GVG, and therefore does not result in an evasion or desire reaction. From the results of the present invention shown in Example 2, it can be seen that the food induces stimulation or compensation effect. Administration of 150 or 300 mg / kg of GVG does not change the CPP response to food even though the stimulating effect of cocaine is weakened. From this confirmation, it can be seen that GVG weakens the compensation / irritation effect of cocaine.

Example 4

Study on the Exercise Activity and Hardness of Experimental Animals

The procedure described in the Materials and Methods section was used in this example. While it is widely accepted that the CPP paradigm distinguishes between stimulant and exercise effects, the inventors of the present invention have evaluated the effect of GVG on rat exercise and hardness. The inventors of the present invention confirmed that the pretreatment using 150 mg / kg or 300 mg / kg dose of GVG did not change the motility activity as compared with the control group pretreated with saline as shown in FIGS. 3A and 3B . In addition, pretreatment with 150 mg / kg or 300 mg / kg dose of GVG did not change the hardness of the mice. The duration of hardening after administration of 300 mg / kg GVG was 1.1 + 0.4 sec (n = 10), which is significantly different from 0.7 + 0.3 sec (n = 10) when treated with saline. n represents the number of animals to be tested.

Example 5

Of rodents and primates ¹¹ C-cocaine level

In this example, the procedure described in Section 6 above was used. To assess the possibility that GVG weakens the action of cocaine by altering cocaine penetration into the brain, the inventors of the present invention investigated the effect of saline and GVG on [ ¹¹ C] -cocine levels in whole rat and primate brains . For rodents, brain [ ¹¹ C] - cocaine levels after intraperitoneal administration of saline and 300 mg / kg GVG are 0.110 ± 0.03 and 0.091 ± 0.02, respectively, which are statistically different. In the case of primates, the pharmacokinetic profile of labeled cocaine binding in striatum was not significantly different from baseline in terms of both absolute uptake and elimination.

Example 6

In this example, the effects of GVG on nicotine-induced changes in extracellular dopamine concentrations were measured in rats that were free to move. The procedure described in Section 7 of Materials and Methods above was performed.

A total of eight rats were examined for each treatment agent mating. The animals were given four treatments paired over 6 days, one for each day. Animals were administered 75 mg / kg of GVG 2.5 hours prior to administration of 0.4 mg / kg of nicotine. On the first day, animals were administered GVG followed by nicotine and confined in a suitable chamber. On the second day, the animals were administered GVG followed by saline and confined in a suitable chamber. The first and second days were repeated three times. Twenty-four hours after administration of the last treatment, the animals were allowed to freely approach the entire behavioral device for 15 minutes and the time spent in the mating chamber and in the chamber was recorded using an automated instrument. The effect of intraperitoneal administration of mg / kg GVG on the acquisition of CCP for rat nicotine investigated in this Example is shown in Table 12 below.

Effect of 75 mg / kg intraperitoneal administration of GVG on acquisition of conditioning site selection for nicotine Pair of treatment Time to send from chamber ¹ Mating chamber Hall chamber ² Nicotine 0.4 mg / kg, sc / excipient ³ 9.4 ± 0.5 5.6 ± 0.5 75, g / kg GVG / nicotine, 0.4 mg / kg, s.c. 6.4 ± 0.3 ⁴ 8.6 ± 0.3 ⁵

¹ Each value represents the mean ± SSM of the time spent in each chamber.

² Only animals were injected with salt water.

^{3 The} excipient is 1 ml / kg 0.9% NaCl or saline solution.

⁴ significantly lower than the nicotine / excipient pair. p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

⁵ significantly higher than the nicotine / excipient pair. p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

Experimental results similar to those summarized in Table 12 are shown in FIG. From Fig. 4, GVG (150 mg / kg) inhibits the nicotine-induced increase in dopamine concentration in mouse-operated rats. A confinement source is obtained from an animal treated with GVG 2.5 hours before nicotine treatment.

Comparative Example

The effect of baclofen on the use of cocaine

The results obtained in Examples 1, 2 and 3 are consistent with previous studies indicating that an increase in GAVA action may attenuate the compensatory / enhancing action of cocaine and other abuse medications. For example, the selective GABA _B agonist baclofen did not reduce the intravenous short-circuiting point of cocaine in male Wistar rats, but was found to have no effect on drug absorption rate. From these results, it can be seen that baclofen weakens the reinforcing effect of cocaine, since a reduction in short-circuiting points indicates a reduction in the incentive for self-administered cocaine.

In addition, it has been hypothesized that an increase in GABA _A receptor function attenuates the self-administration of cocaine as the positive allosteric modulators of the GABA _A receptor complex, chlorodia zoxicase and alprazolam, reduce the rate of cocaine self administration. However, this effect is believed to be associated with an increase in the enhancement value of each unit dose cocaine, which may be due to the fact that chlorodiaxanthide increases the cocaine self-administered short-circuiting point in an incremental rate schedule.

The above confirmation using baclofen was reinforced by recent studies based on the same experiment. As a result of the recent studies, pretreatment of rats with baclofen (1.25-5 mg / kg ip) , The self administration of cocaine can be inhibited for at least 4 hours. It can be seen that microinjection of baclofen into the abdominal epidermis isomorphic to the lateral hypothalamic stimulation electrode of the rat results in a shift in the rat-current curves to the right, which weakens the compensation of electrical stimulation . However, since baclofen does not affect the electrical brain stimulation compensation rate or the level of unreinforced performance, it can be seen that the action of baclofen is independent of changes in motility / hyperactivity.

Recent studies have shown that GVG dose-dependently increases the brain-stimulation compensation threshold of male F344 rats (Kushner et al., 1994), while not giving much nutrition to motility. The increase in brain stimulation compensation threshold resulting from intraperitoneal administration of 2.5 and 5 mg / kg cocaine was significantly neutralized by the 400 mg / kg dose of GVG.

Finally, the CPP response induced by morphine (mg / kg) was considerably attenuated by microinjection (0.1-1 nmol) of baclofen into the abdominal epithelium, an effect similar to that of the GABA _B antagonist 2-hydroxycaprofen . Thus, despite the use of different paradigms to evaluate compensation / enhancement, it can be seen that the activity of the GABA _B receptor weakens the desire for cocaine, morphine, and electrical brain stimulation compensation.

Previously, pretreatment with 1.5 mg / kg ip of prostate beads (increased GABA levels in the brain via metabolism to GABA), which is a GABA-mimetic compound, does not cause preference or avoidance of conditioning sites alone It has been reported that the CPP response to amphetamines does not change. However, it is not possible to compare this confirmation with the present invention because the drugs used to derive CPP, rat varieties, and GABA compounds are different. Also, the pro-bead was only present for 35 minutes. GABA was not at a maximum level during the measurement of amphetamine-induced CPP, since the maximal increase in brain GABA levels after systemic pro-drug administration of beads occurred at 6 hours post-injection.

Taking into account the evidence that an increase in the dopaminergic action of the intermediate limb serves to mediate the compensation / enhancement effect of cocaine, the elimination of the CCP response to cocaine caused by GVG is associated with a change in dopamine activity / action Can be. This hypothesis is supported by our in vivo micronutrient studies in which GVG is administered at a dose of 20 mg / kg (300 and 500 mg / kg ip) or repeated doses (100, 300 and 500 mg / kg ip) dependent increase in the extracellular DA levels of NACC and striatum generated by cocaine of the &lt; RTI ID = 0.0 &gt; ip &lt; / RTI &gt; (Dewey et al., 1998). At the same time, the sensitivity of the DA receptor after administration of GVG can not be a cause of cocaine aggravation because it has been shown that repeated administration of GVG does not alter the D ₁ or D ₂ sensitivity of the mouse striatum. However, there is no evidence for the effect of GVG on other DA receptors (D ₃ , D ₄ , and D ₅ ). Alternatively, cocaine can alter the release of neurotransmitters such as DA by altering GABA _B receptor function, and cocaine can be neutralized by GVG through increased levels of GABA and stimulation of GABA _B receptors.

In addition, repeated administration of cocaine has been shown to reduce the effects of pre-synaptic GABA _B auto and heteroreceptors on the lateral bulbar nuclear neurons of rat brain slices. Thus, an inhibition termination action can occur and the release of neurotransmitters can be increased. In addition, baclofen can weaken the action of DA and can cascade the action of cocaine. This fact is indirectly supported by the reference of Lacey et al. (1998), which suggests that the extrinsic flow induced by DA in the substantianergic compacter neurons of rats is the maximum flow produced by the baclofen As shown in Fig.

Several interpretations of the results of the present invention are possible. First, by increasing the metabolism of cocaine, GVG can reduce the amount of cocaine reaching the brain, thereby alleviating the neurochemical effects of cocaine and ultimately the behavioral effects of cocaine. However, this interpretation can not be made because the level of ¹¹ C-cocaine in rats or primates pretreated with GVG (300 mg / kg) has not changed. In addition, cocaine is mainly metabolized by plasma collinease, whereas GVG is excreted in the urine without change, making pharmacokinetic interactions impossible.

Drugs that increase the action of GABA have been reported to cause sedation or ataxia. It is therefore reasonable to assume that GVG can neutralize the action of cocaine nonspecifically by causing the abovementioned behavioral side effects. However, from the study results of the present invention, it can be seen that the above-mentioned theory can not be supported since GVG does not cause hardening or changes motility activity significantly. In addition, from the above-mentioned examples, it can be seen that the antagonistic action against the cocaine action is not the result of the equilibrium avoidance action because GVG causes avoidance of the conditioned place. In addition, it can be seen that GVG does not induce CPP alone, so it does not move the animal's preference from a cocaine-matched environment to a GVG-matched environment.

It has been found that GVG administration can alter the food consumption of rats. Based on this fact, it can be seen that GVG can reduce or attenuate the pleasure value of cocaine-induced compensation in addition to natural compensation. However, studies of the present invention have shown that GVG at doses of 150 and 300 mg / kg do not change CCP for food.

There is evidence that the state of the Conditioning Place Preference (CPP) paradigm depends on the emotional and memory-improving properties of the reinforcement during the test. Thus, the inhibition of GVG on the expression and acquisition of cocaine-induced CPPs may interfere with memory, thereby interfering with the combination of cocaine-induced positive stimulation values and appropriate stimuli. In fact, certain drugs that increase the action of GABA are known to be able to impair memory. However, since the GVG does not affect the conditioning of the food place, the above hypothesis can not explain the antagonism of GVG to cocaine action in the CPP paradigm.

The GVG doses of 112, 150 and 300 mg / kg were found to counteract the acquisition and expression of cocaine-induced CPP. By comparison, it can be seen that GVG does not induce CPP or conditioned locus repelling reactions and therefore does not antagonize the action of cocaine by causing CPP-alone reactions or by attenuating CPP by the occurrence of repellent effects. In addition, GVG does not induce hardness and does not change the stimulation value of food. There is evidence that cocaine-related stimuli recur a drug-seeking state or cravings of detoxifying cocaine addicts. Measured in the absence of cocaine, the expression of CPP for cocaine is neutralized by GVG. From these results, it can be seen that the cravings of cocaine addicts can be attenuated by GVG.

The delivery of dopamine in the NACC was specifically related to the enhancement of cocaine. In the PET studies described above, measurements were made on striatum rather than NACC. Neurotransmission of DA in striatum was not associated with compensation and enhancement of cocaine, but the effects of cocaine on extracellular DA levels are quantitatively similar to those of the two sites. Also, in vivo microdialysis studies of the present inventors have shown that GVG attenuates cocaine-induced increases in extracellular DA levels to similar degrees to each other at the two sites (Dewey et al., 1997; Morgan and Dewey, 1998).

In the present invention, two different species of rodents and primates were used to perform imaging and behavioral experiments. However, the intermediate cortical marginal DA systems are identical to each other in neural anatomy and neurophysiologically. In addition, the biochemical effects of cocaine on extracellular DA as measured by in vivo microdialysis are similar to those of the two species, and both the animal and primate are easily self-administered with cocaine (Morgan et al., 1998).

Based on the experimental results of the present invention, inhibition of behavior in the CPP paradigm was secondary to a GVG-induced increase in GABA inhibition in the mid-cortical marginal DA system, due to the weakening of the cocaine effect on DA in the brain.

GVG provides a conceptual advantage of inhibiting the stimulation of stimulation and biochemical effects of cocaine by irreversibly inhibiting GABA-T and making the synthesis of the enzyme relatively slow. From recent reports of cocaine abusers, it can be seen that gabapentin, an anti-convulsant drug that weakens transmission of GABA via an unknown mechanism, reduces cocaine withdrawal and cravings. In addition, from these data, it can be seen that drugs that selectively target GABA system are beneficial for the treatment of cocaine poisoning. More specifically, GVG-induced GAGB-T inhibitors that increase brain extracellular GABA levels represent an effective drug and novel method for the treatment of cocaine poisoning.

Example 7

In fact, sensitization is observed in all addictive drugs. Sensitization appears to play a role in the pathogenesis of poisoning. In this example, the effect of saline and 150 mg / kg ip dose of GVG on expression of cocaine-induced arousal behavior after cocaine sensitization regimen was measured in rats that were free to move.

Animals were administered 15 mg / kg i.p. of cocaine and stereotypy was measured in a standard exercise cage. For six consecutive days, animals in the cage were dosed once daily with 150 mg / kg ip of cocaine. After 8 days, the animals were again dosed with mg / kg i.p. of cocaine and their anomalies were measured. Five grades were used to assess odds ratios, and the grading person was not allowed to see treatment with each animal. It was found that GVG was eliminated at the dose of 150 mg / kg i.p. 2.5 hours before cocaine administration, indicating that the expression of cocaine-induced sensitization was eliminated. The results are shown in Table 13 below.

Saline for the expression of cocaine-induced ischemia after cocaine sensitization regimen and 150 mg / kg i.p. Effect of Dose GVG Score of the first day Treatment agent 2 hours before the measurement of syneresis Suffering on the 15th day 2.5 ± 0.4 1 ml / kg i.p. 0.9% NaCl 4.1 ± 0.5 * 2.9 ± 0.4 150 ml / kg i.p. GVG 2.3 ± 0.6

* Significantly higher compared to day 1, p <0.005, Student's test.

The following experiments are intended to measure the effect of GVG on nicotine-induced increases in NACC DA, as well as the effects on conditions associated with these biochemical effects. Specifically, experiments were conducted to: 1) measure the effect of GVG and nicotine on extracellular NACC DA using free-flowing native and chronic nicotine treated animals with bioequivalent hemodialysis; 2) measuring the effect of GVG on the nicotine-induced reduction of ¹¹ C-lacrolide binding of anesthetized female beekeepers using positron emission tomography (PET); 3) investigating the effect of GVG on nicotine-induced CCP.

Example 8

Effect of GVG on nicotine-induced increase in NACC DA

1. Studies on microdialysis of rodents

In this example, nicotine was used as a toxic drug. Animals in Group 1 received nicotine (0.4 mg / kg, sc) 2.5 hours before GVG (75, 90, 100 or 150 0.4 mg / kg i.p.). As a separate experiment, animals in group 2 received nicotine (0.4 mg / kg, sc) twice daily for 21 days. During the study period, GVG (100 mg / kg) was administered 2.5, 12 or 24 hours before the administration of nicotine (0.4 mg / kg, sc). For all studies, animals were placed overnight in a microdialysis bowl and sprayed with artificial cerebrospinal fluid (ACSF) through a microdialysis probe at a flow rate of 2.0 μl / min. After each study, animals were killed and the brain The probe was removed by dividing it into individual pieces.

In group 1 animals, nicotine increased the extracellular DA concentration of NACC by about 100% at 80 minutes after administration (FIG. 5A). That is, the DA level increased to about 200% of the reference level. At about 160 minutes after administration, DA returned to baseline levels. The dose-dependent form of GVG inhibited the DA increase as shown in Figure 5A. At 75 mg / kg, GVG did not affect the nicotine-induced increase in DA, but at 90 mg / kg, GVG increased DA by approximately 50% and completely eliminated any DA increase at 100 mg / kg. Also, the highest dose of 150 mg / kg completely eliminated the increase (data not shown). In particular, GVG did not lower the baseline DA level before administration of nicotine at the above three high doses (90, 100, or 150 mg / kg). The lowest dose (75 mg / kg) did not affect baseline DA levels and therefore did not affect the ability of nicotine to increase extracellular NACC DA.

In the animals of group 2, nicotine increased the extracellular NACC DA level to the same extent within the same period of time as the measurement period of group 1 (about 100% increase from the baseline, Figure 5b). As confirmed in Group 1, GVG (100 mg / kg) completely abolished nicotine-induced increase in extracellular DA when administered 2.5 hours before nicotine administration. However, when administered 12 hours prior to administration of nicotine, nicotine increased the extracellular DA level by about 25% compared to baseline (Fig. 5B). Group 2 animals receiving GVG 24 hours prior to administration of nicotine increased DA levels to values similar to those of control animals (Figure 5b). Consistent with our previous confirmation (Dewey et al., 1997), GVG did not change overall motor activity during the 2.5 hour pre-treatment interval. However, in all animals, nicotine increased total motor activity regardless of the dose of GVG.

Example 9

2. The nicotine-induced CPP

Description of the CPP device

The CPP apparatus is made entirely of plexiglass except that the floor of one of the paired chambers consists of a stainless steel plate with an edge and edge spacing of 5 mm and a hole (0.5 mm diameter). These two paired chambers have different visual and tactile stimuli. One chamber was a light blue color with a stainless steel floor and the second chamber was a light blue color with a smooth plexiglass floor and 2.5 cm wide horizontal black strips, the strips being 3.8 cm apart from each other. The two chambers were separated from each other by a third neutral connection tunnel (10 x 14 x 36 cm) with plexiglass walls and plexiglass bottom. The visual and tactile stimuli are balanced to one another so that the animals do not experience significant ancillary preferences prior to conditioning.

Effect of GVG on expression of CPP in rodents

The conditioning process consisted of 20 sessions that were performed continuously over 20 days. The first three sessions were taming sessions during which animals were treated for five minutes daily and exposed to the sight and sound of the laboratory. Sixteen sessions of eight pairs were then performed using one excipient / excipient (1 mg / kg i.p. 0.9% saline, n = 10) or seven saline-nicotine (0.4 mg / kg s.c.) groups. One half of the test group animals received nicotine before exposure to the blue chamber and the other half received saline prior to exposure to the blue and black strip chambers. The animal receiving the vehicle or nicotine was injected and allowed to access the rest of the chamber for 30 minutes in the appropriate compartment via the Guillotine Flexi Glass door. The final session (day 20) is a test session, 30 minutes before the experiment, animals were treated with one of the following treatments: 1) saline or 2) GVG (18.75, 37.5, 75 or 150 mg / kg ip ). The openings of the two paired chambers were opened and the animals were allowed to move freely between the two chambers for 15 minutes. The time spent in each chamber was recorded using an automatic infrared beam that was electronically connected to the timer.

Effect of GVG on acquisition of CPP

Animals were tame as described above. Animals were administered saline or GVG (37.5 and 75 mg / kg i.p.) 2.5 hours prior to nicotine administration. Next, the animals were placed in a suitable chamber for 30 minutes. This process was repeated over 16 days for 8 pairs. On the day of testing, animals were placed in the CPP unit and the time spent in the chamber was recorded to allow free access to all CPP chambers.

When the brine was administered, there was no preference for the chamber. However, nicotine (0.4 mg / kg sc) caused a statistically significant and reliable CPP response, with animals receiving 9.6 + 0.6 min in the paired chambers (nicotine), while the animals in the unpaired chamber Saline) spent 5.4 + 0.6 minutes (Tables 14 and 15). As a result of statistical analysis of the expression data, F (5,50) = 21.6, p <0.001). Post hoc analysis confirmed that GVG at doses of 18.75, 37.5, 75.0, or 150 mg / kg, but not saline, eliminated the expression step of nicotine-induced CPP (Table 14).

As a result of analysis of acquired data, the processing effect of F (3,32) = 11.8, p <0.05 was confirmed. Post hoc analysis showed that GVG (37.5 mg / kg) did not significantly inhibit the acquisition of nicotine-induced CPP (Table 15). By comparison, the 75 mg / kg dose of GVG significantly eliminated the step of obtaining nicotine-induced CPP (Table 15).

Effect of saline and GVG on the expression of conditioned place selection reaction for (-) nicotine at 0.4 mg / kg s.c. Mating treatment agent Drugs administered on the test day Time spent in chamber Paired chambers Unpaired chamber Brine / brine Brine ² 7.4 ± 0.3 ¹ 7.6 ± 0.3 Saline / nicotine Brine 9.6 ± 0.6 5.4 ± 0.6 Saline / nicotine GVG, 18.75 mg / kg ³ 7.5 ± 0.7 * 7.5 ± 0.7 Saline / nicotine GVG, 37.5 mg / kg 6.8 ± 1.0 ** 8.2 ± 1.0 Saline / nicotine GVG, 75 mg / kg 6.4 ± 0.3 ** 8.6 ± 0.3 Saline / nicotine GVG, 150 mg / kg 5.0 ± 0.9 ** 10.0 ± 0.9

¹ Each value represents the mean value ± SEM of the time (minutes) spent in each chamber. A total of 8-10 rats were investigated for each treatment pair. Eight pairs of treatments consisting of nicotine and brine were administered to all animals before the test day. On the day of testing, animals were either given saline or GVG 2.5 hours before the animals were placed in the CPP device.

^The saline was 0.9% saline at 1 ml / kg sc.

* Significantly lower than the brine / nicotine pairs paired with salt water on the test day. p &lt; 0.05, ANOVA and Student-Newman-Keuls test.

* Significantly lower than the brine / nicotine pairs paired with salt water on the test day. p &lt; 0.01, ANOVA and Student-Newman-Keuls test.

Effects of saline and GVG on the acquisition of conditioned place selection reactions for (-) nicotine at 0.4 mg / kg s.c. Mating treatment agent Time to send from chamber (minutes) Paired chambers Unpaired chamber Brine / brine ² 7.3 ± 0.3 ¹ 7.7 ± 0.3 Saline / nicotine 9.6 ± 0.6 ¹ 5.4 ± 0.6 Nicotine / GVG, 37.5 mg / kg 8.8 ± 0.5 6.2 ± 0.5 Saline / GVG, 75 mg / kg 6.9 ± 0.9 * 8.5 ± 0.9

¹ Each value represents the mean value ± SEM of the time (minutes) spent in each chamber. A total of 8-10 rats were investigated for each treatment pair. Animals were pretreated with either saline, GVG at 37.5 or 75 mg / kg ip, and after 2.5 hours, each animal was dosed with 0.4 mg / kg sc of saline (saline / brine) Nicotine was administered. Eight matings were performed for each animal.

^The saline was 0.9% saline at 1 ml / kg sc.

* Significantly lower than the brine / nicotine pairs paired with salt water on the test day. p &lt; 0.05, ANOVA and Student-Newman-Keuls test.

Primate PET study

For all imaging studies, mature female baboons (n = 16) (Papio anubis, 13-18 kg) and carbon-11 labeled lacrolpride ( ¹¹ C-lacopride) were used. Animals were divided into five groups as shown in Table 16. The control animals (Group 1) were injected twice with ¹¹ C-lactoferred without any drug intervention to determine the test / retest variability of the measurements. These data have been reported previously (Dewey et al., 1998). Group 2 animals received only GVG (300 mg / kg) 2.5 hours before the second injection of ¹¹ C-lacrofenide. As with group 1 animals, this data was previously reported (Dewey et al., 1992). Group 3 animals received only nicotine (0.3 mg total, approximately 0.02 mg / kg) 30 minutes before the second injection of ¹¹ C-lactoferred. In the study of GVG / nicotine, GVG was administered intravenously at a dose of 100 mg / kg (Group 4) or 300 mg / kg (Group 5) 2.5 hours prior to administration of nicotine. Nicotine (0.3 mg total) was administered 30 minutes before the second injection of ¹¹ C-lacronpride. Arterial blood samples were obtained from these studies and analyzed for unchanged ¹¹ C-lacronpride using selected plasma samples. During the interval between isotope injections, animals were not taken out of the gantry. Data analysis was performed using the previously published Logan method (Logan et al., 1990).

Each primate (n = 16) was injected twice with ¹¹ C-lacrolpride. The first injection was used as the baseline for the second injection and the second injection was performed after the administration of GVG, nicotine, or both. Test / Retest The test / retest variability of the method was measured by administering a placebo (0.9% saline, 1 ml / kg) 30 minutes before the second radial target was injected into the primate (n = 7, Table 16). All other primates (n = 9) were systemically injected with GVG, nicotine, or both before injecting ¹¹ C-lacrolpride.

As previously reported (Dewey et al., 1998), the variability of the mean distribution volume (DV) ratio of test / retest labeling of the label raclopride in the primate striatum was slightly higher than 7% (Table 17). Administration of GVG (300 mg / kg, Group 2) increased the mean DV ratio by 18% (Table 17). These data are consistent with micronutrient studies that demonstrate that GVG doses dependently reduce extracellular DA levels in animals that are free to move. However, administration of nicotine (Group 3) resulted in the opposite effect of GVG and significantly reduced the mean DV ratio by 12% (Table 17). This result is also consistent with the microdialysis data of the present invention demonstrating that nicotine increases the extracellular DA of an animal that is free to move. Upon sequential administration, GVG (100 mg / kg, Group 4) eliminated the reduction in mean DV ratio caused by nicotine (Group 3) alone. When GVG was administered at this dose, the mean DV ratio was similar to the test / retest results (9%, Table 17) obtained in Group 1 animals. However, when administered at a dose of 300 mg / kg (Group 5), the mean DV ratio of the representative lacrolpride was significantly higher by 15% as compared to the test / retest results, and the Group 2 animals receiving only GVG (Table 17). &Lt; tb &gt; &lt; TABLE &gt;

GVG, nicotine or both did not change the systemic metabolic rate and area distribution of the marker luciferide.

Primate PET study group group Condition One Test / retest (no medication) 2 GVG (300 mg / kg) 3 Nicotine (0.3 mg) 4 GVG (100 mg / kg), nicotine (0.3 mg) 5 GVG (300 mg / kg), nicotine (0.3 mg)

Effect of Drug Administration on Average DV Ratio group % Change in average DV ratio One 7.16 ± 1.2 2 18.8 ± 3.2 3 -12.3 ± 2.6 4 9.45 ± 2.1 5 15.1 ± 2.8

Analysis of experimental results obtained in Example 9

In this example, the inventors of the present invention have demonstrated that nicotine (0.4 mg / kg s.c.) increases NACC DA of free-moving animals by about 100% or 200% after about 80 minutes of administration. As a result of previous microdialysis studies, it has been reported that administration of nicotine at doses of 0.6 or 0.8 mg / kg sc increased the extracellular DA levels of NACC by 220% and 179%, respectively (Di Chiara and Imperato, 1988; Imperato Et al., 1986; Brazell et al., 1990). Although not directly comparable, the results of the present invention are in clear agreement with the previous reports. Also, administration of nicotine to animals exposed to chronic nicotine according to the present invention resulted in a 90% increase in extracellular NACC levels. This confirmation is consistent with previous data (Damsma et al., 1989) indicating that chronic nicotine administration does not cause resistance or sensitization to acute nicotine administration.

With regard to the identification of the present inventors using GVG, the present inventors have demonstrated that GVG dose-dependently inhibits the nicotine-induced increase of NACC DA in natural and chronic nicotine treated animals. This is the first time we have reported the action of GVG. At a dose of 75 mg / kg, GVG is ineffective because nicotine increases extracellular DA by approximately 200%. On the other hand, the GVG dose of 90 mg / kg inhibited the increase of extracellular DA by about 50%. At the two maximum doses studied (100 and 150 mg / kg), GVG completely inhibited the increase in extracellular NACC DA levels. Previously, the inventors of the present invention demonstrated that acute injection of GVG (300 mg / kg i.p.) reduced the cocaine-induced increase in NACC DA level by 25% (Dewey et al., 1998). However, chronic treatment with a similar dose of GVG was even more inhibited (Morgan and Dewey, 1998). Taken together, these data indicate that the dose of GVG required to significantly attenuate the drug-induced increase at the NACC DA level depends on the dosage of the drug in addition to the type of drug used (eg, cocaine, nicotine) .

In addition, the data of the present invention demonstrate that the effect of GVG is related to a dose-dependent ability to lower the baseline DA level before drug administration. For example, the 75 mg / kg dose did not affect the nicotine-induced increase in baseline DA and DA. However, when the dose was 90 or 100 mg / kg, GVG reduced the baseline DA level by 50% or eliminated the effect of nicotine. Thus, a dose-dependent reduction in nicotine- or cocaine-induced increase in NACC DA is believed to be due to a pre-reduction in the baseline DA concentration that accompanies an increase in endogenous GABA produced by GVG. This fact is consistent with data indicating that an increase in the action of GABA reduces the DA of NACC.

As an extension of our previous work with GVG and cocaine, we investigated the transient pathways of the effect of GVG on the nicotine-induced increase of NACC in chronically treated animals using nicotine for 21 days. Administration of GVG at a dose of 100 mg / kg 2.5 hours prior to nicotine administration resulted in complete elimination of the drug-induced increase in NACC DA. However, nicotine increased the extracellular DA by approximately 25% when the same dose was administered 12 hours prior to administration of nicotine.

GVG did not affect the nicotine-induced increase of NACC DA when administered at the same dose as above at 24 hours before administration of nicotine. Clearly, from the inventor's microdialysis and behavioral data, it can be seen that a very small change in GATA-B inhibition caused by increasing the dose of GVG has a great effect on the inhibition of the nicotine-induced increase of NACC DA and CPP .

These data are of particular interest in terms of the rate of synthesis of GABA-T, the half-life of GVG in rodents, the duration of action with respect to GABA, and the sharp dose-dependent curves. Previous studies have shown that the biological half-life of GABA-T in rodent brains is 3.4 days, while the half-life of GVG in the brain is about 16 hours. In addition, total brain GABA levels do not begin to decrease until 24 hours after acute GVG administration (Jung et al., 1977). GABA inhibition of the mesothecaemal compensatory pathway from the imbalance between the sustained GABA levels measured in the brain 24 hours after the single administration of GVG and the normal response to the nicotine administration observed at the same time is a simple reflection of the entire GABA level of the brain It is not. That is, the total brain GABA level in the brain continues to increase significantly after 24 hours of GVG administration, but small differences between the specific pathways can be masked by the above comprehensive measurement. Finally, it can be seen that the GABA receptor has been desensitized to GABA over the 24 hour period, but the inventors do not know the evidence of the GABA system that can support this hypothesis.

In the study of the present invention, the inventors have demonstrated that eight saline-nicotine pairs cause a reliable CPP reaction. The results of the present invention are consistent with previous studies (Fudala et al., 1985; Fudala and Iwamoto) that nicotine (0.1-1.2 mg / kg s.c.) causes a dose dependence of the CPP response of male Sprague-Dawley. We also found that Lewis animals, rather than F344, exhibited CPP responses to nicotine after 10 mating pairs (Horan et al., 1997). However, previous studies have shown that the four nicotine-excipient pairs failed to induce the CPP response in male hooded animals (Clake and Fibiger, 1987). Thus, nicotine-induced CPPs are believed to depend on animal species, but this can be confused by the fact that the above-cited studies utilized different numbers of matings. The nicotine-induced CPP response reported in the present invention is consistent with the notion that nicotine exerts a positive effect on stimulus motivation behavior.

From these data, it can be seen that GVG can inhibit the biochemical and behavioral effects of nicotine using the CPP paradigm. From the CPP data, it can be seen that the 18.75 mg / kg dose of GVG removes the expression of the CPP response caused by nicotine. Furthermore, it can be seen from the data of the present invention that GVG at a dose of 75 mg / kg, rather than a dose of 37.5 mg / kg, inhibits the acquisition of the CPP response to nicotine. Based on the confirmation of the effects of these doses, the dosage of GVG required for the treatment of withdrawal may be 250-500 mg per day (2-4 g per day for epilepsy), which is administered to patients with epilepsy Is significantly lower than the amount of

We have previously shown that GVG (75-300 mg / kg ip) alone does not cause CPP or avoidance (Dewey et al., 1998), so the effect of GVG on nicotine- It is not judged to be related to the effect. In addition, since GVG does not inhibit food compensation or motor activity at high doses of 300 mg / kg, it does not seem to eliminate nicotine's behavior by interfering with memory or motor activity (Dewey et al., 1998) .

Finally, GVG was not self-administered by rhesus monkeys and the animals after chronic GVG treatment did not show withdrawal symptoms (Takada and Yanagita, 1997). Thus, unlike other drugs used in drug therapy for certain addictions (eg, methadone, anabus), GVG is not addictive by itself and does not produce significant avoidance effects.

Using GVG to attenuate the acquisition of CPP response to nicotine can be judged as a decrease in the positive stimulation value of nicotine. From these data, it can be seen that GVG reduces the tendency of animals to acquire a positive stimulatory effect after administration of nicotine. Importantly, from the results of the present invention, it can be seen that the dose of GVG required to inhibit the expression step of the CPP response generated by nicotine was 1/4 of that required to inhibit the acquisition of the CPP response. This confirmation is consistent with our previous study (Dewey et al., 1998) that a higher dose of CPP is required to inhibit acquisition, in contrast to the expression of CPP for cocaine. Descriptions of these differences are not yet known. GVG weakens the expression of the CPP response to nicotine. Thus reducing the drug-craving state of the animal that has already obtained the positive stimulation value of nicotine.

Thus, from the data of the present invention, it can be seen that GVG is more effective in suppressing craving for nicotine than suppressing the positive stimulation value or compensating action of nicotine. Finally, at the highest dose tested (150 mg / kg), GVG caused a significant repulsion on the day of testing (Table 15), with animals receiving 5.0 + 0.9 min for paired chambers (nicotine) While the unpaired chamber (brine) spent 10.0 + 0.9 minutes. From these data it can be seen that high doses of GVG can be treated with nicotine and there may be a ceiling effect that makes the animals tested in the drug free state to have a repellency. Such data may be relevant to ascertain dose limits to be tested in human clinical trials.

Based on our theory of the CPP paradigm, the data of the present invention supports the following results. In the CPP paradigm, animals are tested in the absence of drugs to determine whether they previously prefered the nicotine-administered environment or the salt-fed environment. If the animals consistently select the nicotine-related environment when the drug is released, it is concluded that the nicotine desire value approaches the drug-free state because it is coded in the brain (Gardner, 1997). In fact, on the day of testing, the approaching and association of animals with a drug-paired chamber can be considered drug-craving behavior. Essentially, environmental stimuli or other stimuli that are neutral or non-iron polar are iron salience by repeating mating with nicotine. Next, when the animal is exposed to this stimulus again, a CPP reaction occurs. That is, the stimulation can induce a drug effect. Thus, drug-related stimuli cause a faba-like conditioning reaction.

In addition to pharmacologic factors, nonpharmacologic factors are known to play a role in mediating the stimulation value of addictive drugs (Jarvik and Henningfield, 1988). Indeed, it has been clinically proven that detoxified addicts can be recurrent if exposed to stimuli associated with drug use (Childress et al., 1986a; Childress et al., 1988; Ehrman et al., 1992; O'Brien et al., 1992; Wikler, 1965). Thus, from the above data it can be seen that GVG inhibits the expression of nicotine-induced CPP responses and thus inhibits nicotine craving or craving. Therefore, GVG is effective in treating people who want to quit smoking. Also from these data, GVG is effective in eliminating the expression of the CPP response to nicotine, and can weaken the craving for environmental stimulation associated with smoking.

The primate PET data of the present invention demonstrate that prior cognition using multiple drug doses (Dewey et al., 1993; Seeman et al., 1989) and that ¹¹ C-lacrolide binding is sensitive to both increase and decrease of synaptic DA It is a match. As evidenced in Group 3 animals (Table 17), the mean DV ratio after administration of nicotine decreased relative to baseline. These reductions exceeded the test / retest variability of the labeling clavulanate and were lower than those obtained using GBR-12909 (Dewey et al., 1993). Pretreatment with GVG at a dose of 100 mg / kg 2.5 hours prior to administration of nicotine resulted in a value similar to the mean DV value of Group 1 animals (Table 17). However, when the dose of GVG was increased to 300 mg / kg, the mean DV value increased to a value corresponding to the value of the animals in group 2. These data show that a lower dose of GVG leads to a decrease in synaptic dA corresponding to an increase caused by nicotine, while a reduction in the dose of GVG far exceeds the ability of nicotine to increase DA . This data is supported by our microdialysis studies, the higher the dose of GVG, the greater the extracellular DA decrease in free-moving animals.

From the microdialysis and PET results with CPP data, it can be seen that increasing DA in NACC is the basis for addictive drug addiction. First, from data on cocaine with this data, in vivo microdialysis studies or PET measurements of endogenous DA can not necessarily be deduced to determine the efficacy of drugs used in the treatment of diseases that are thought to have neurotransmission specificity . Second, from both the microdialysis data and PET data, it was demonstrated that the 100 mg / kg dose of GVG completely inhibited the nicotine-induced increase of the NACC DA level, whereas the 75 mg / kg dose was ineffective. By comparison, a low dose of 18.75 mg / kg of GVG completely abolished the expression step of nicotine-induced CPP, whereas the 75 mg / kg dose of GVG abolished the acquisition step.

Based on the dose-response curve obtained from the microdialysis data, it can be seen that the 18.75 mg / kg dose of GVG has an effect on the nicotine-induced increase of NACC DA. Also, in the case of cocaine, the use of GVG at a dose of 300 mg / kg inhibits the cocaine-induced increase in NACC DA level by 25%, whereas the use of 150 mg / kg dose of GVG results in a decrease in cocaine-induced CPP (Dewey et al., 1997; 1998).

The data of the present invention can be interpreted in two or more ways. First, the differential change in DA after NACC after drug administration may be the cause of certain drug addiction. In fact, several addictive drugs have been reported to be able to alter the DA level of brain regions other than NACC (including the tonsils, striatum, and frontal cortex) (Hurd et al., 1997; Dewey et al., 1997; Di Chiara and Imperato, 1988; Marshall et al., 1997). Second, neurotransmitters other than DA can play a crucial role in the addiction of abuse drugs. For example, in mice lacking DA and 5-HT carriers, the CPP response to cocaine is maintained (Sora et al., 1998; Rocha et al., 1998). In addition, neurotransmitters such as 5-MT, acetylcholine, enkephalin and glutamate are known to play a role in mediating the action of addictive drugs including nicotine (Bardo, 1998; Gardner, 1997). Taken together, these data suggest that GVG inhibits the effects of nicotine and cocaine by altering DA in areas other than NACC. At the same time, GVG can inhibit other neurotransmitters that mediate DA directly or mediate addictive drug effects. Other studies are underway to evaluate the multiple effects of GVG on other neurotransmitters.

Previously, the inventors of the present invention have demonstrated that the ability of GVG to attenuate the cocaine-induced increase of NACC DA is completely abolished by treatment of the animal with the selective GABA _B receptor antagonist SCH 50911 (Bolser et al. 1995). The SCH 50911 is a substance that does not significantly change the DA level when administered alone. It can be seen that GVG increases the level of GAGB and abolishes the action of nicotine by stimulating GABA _B receptors. This fact indicates that administration of baclofen, which is a selective GABA _B agonist (Bowery and Pratt, 1992; Kerr et al., 1992), into VTA significantly reduces the CPP response of animals caused by systemic morphine (Tsuji et al., 1995) It is consistent with the data. In addition, systemic administration of baclofen gradually attenuates self-administration of cocaine (Robert et al., 1996, 1997).

It may be argued that GVG can weaken nicotine's drugs and behavior by simply changing the amount of nicotine that enters the brain effectively by changing the blood-brain barrier permeability or by increasing the rate of systemic nicotine metabolism. This argument is impossible for a variety of reasons. First, GVG did not affect the blood-brain barrier transport of ¹¹ C-cocaine, an alkaloid that was found to increase NACC DA, in both the rodent and primate brains. Second, while GVG is secreted through the kidneys in an unaltered form (Grant and Heel, 1991; Porter and Meldrum, 1998), nicotine is metabolized by enzymes in the liver. Finally, GVG does not interact with the liver microsomal enzymes (Grant and Heel, 1991; Porter and Meldrum, 1998) and can not induce or inhibit the enzyme.

The size of the NACC was much smaller than the resolution of the inventors' tomography machine and was analyzed using a special method. Therefore, the analysis of the present invention included striations and cerebellum. Marshall et al. (1995) described that nicotine equally increases DA in both NACC and striatum, but our microdialysis data show that GVG equally decreases in DA concentration in both regions (Dewey et al., 1997). From these primate data, it can be seen that the imaging method can be used to assess the action and outcome of drug administration in a fully live brain.

This method of medical imaging also provides a unique means of knowing the interactions between neurotransmitters that are operatively linked in both the primate brain and the human brain.

From the vast literature supporting the basic theory that neurotransmitters interact in a neuroanatomical lesion that is functionally distinctive and site-specific, it is possible to obtain new (or more) neuropsychiatric It can be seen that the treatment method can be practiced in many countries that have knowledge of the basic principles and literature theory. Indeed, changes in neurotransmitter concentrations can be a pathogenesis of specific disorders, but disease development and symptomatic development can be linked to compensatory or disease-induced changes in other neurotransmitters that are operatively linked to the initial target. In accordance with this theory, the inventors of the present invention have developed a novel therapeutic method for specifically altering one or more neurotransmitters by targeting other neurotransmitters. The identification of the present inventors, obtained using nicotine, cocaine, methaamphetamine, alcohol and GVG, has significant utility in the treatment of mammals that are addicted to abuse drugs.

Example 10

Effect of GVG on methaamphetamine-induced increase of NACC DA

In this example, the effect of GVG on the metam amphetamine-induced changes in NACC dopamine concentration was studied in 6-8 freely-moving mice. 1.25 mg / kg i.p. Dose and 2.5 mg / kg i.p. dose of methamphetamine were administered to the animal. Methaamphetamine increased the extracellular DA concentration by about 2500% compared with the baseline level after 100 minutes after the administration of 2.5 mg / kg, and increased the DA level by about 1500% compared to the baseline level after administration of 1.25 mg / kg (Fig. 6). DA returns to baseline levels approximately 200 minutes after administration.

When GVG was administered prior to administration of meta-amphetamine, GVG dose-dependently inhibited the DA increase as shown in FIG. At a dose of 300 mg / kg, GVG inhibited the DA increase by approximately 38%, and at a dose of 600 mg / kg inhibited the DA increase by approximately 58%. From these data, it can be seen that GVG inhibits the methaamphetamine-induced increase in the extracellular dopamine concentration of NACC.

Thus, from the above data it can be seen that the order of nicotine, cocaine and methamphetamine in increasing NACC DA is methamphetamine (2500%)> cocaine (450%)> nicotine (90%), The order of magnitude of the acute dose of GVG required to inhibit the drug-induced increase in DA is similar.

Example 11

Effect of GVG on ethanol-induced changes in NACC DA

In this example, the effect of GVG on ethanol-induced changes in NACC dopamine concentration was studied in 6-8 free-moving mice. 1.0 g / kg i.p. A dose of ethanol was administered to the animal. Ethanol increased the NACC DA concentration by about 200% compared to the baseline level at 125 minutes after ethanol administration.

When GVG at a dose of 300 mg / kg was administered, the increase in DA was inhibited by about 50% (Fig. 8). In addition, when administered at a dose of 100 mg / kg, GVG inhibited approximately 40% of the alcohol's ability to increase the nuclear abinance of the free-moving rat (data not shown). From these data, it can be seen that GVG inhibits the ethanol-induced increase of the extracellular dopamine concentration of NACC.

Example 12

Effect of GVG on NACC DA- induced cocaine / heroin induction

In this example, the inventors of the present invention evaluated the effect of GVG on the increase of NACC DA after cocaine / heroin (speedball) administration. In vivo microdialysis was performed using mature male Sprague-Dawley (Taconic Farms) as previously presented (Morgan and Dewey, 1998). Dopamine reuptake inhibitor cocaine (n = 6-8) was intraperitoneally administered at a dose of 20 mg / kg, while the indirect dopamine releaser heroin (n = 6-8) was administered at a dose of 0.5 mg / Was administered intravenously. In a study to evaluate the synergistic effect of cocaine / dopamine combination (n = 6-8), both drugs were administered at the same doses as those used in the single dose study. Cocaine alone significantly increased extracellular DA levels at approximately 380% of baseline levels after 60 minutes of dosing. DA returned to baseline after 120 minutes. By comparison, heroin increased the NACC DA level by 70% 60 minutes after administration, and returned to baseline levels after 140 minutes. However, when combined, both drugs increased the NACC DA level by 1000% 180 minutes after administration, which returned to baseline levels within 200 minutes after reaching the peak value (FIG. 9). This increase is significantly different from the increase by cocaine or heroin alone (P &gt; 0.001).

This neurological synergism becomes apparent in terms of the time it takes to reach the baseline level after reaching the peak, in addition to the NACC DA increase, as compared to the additive effect. Each drug produced a maximum increase in DA within 60 minutes after administration. However, when the two drugs are combined, the maximum increase is three times longer than when the single drug is used. Also, the time taken to reach the baseline value is significantly longer than when each drug is used alone. From this confirmation, it can be seen that when the two drugs are used in combination, the taking-out period is considerably longer as compared with the case of using alone.

As for the absolute grade of response, GVG completely abolished the synergistic effect after administration of the combined drug. In animals treated with GVG (300 mg / kg i.p.) 2.5 hours prior to administration of the combination drug, NACC DA increased about 500% 180 minutes after administration of the combination drug (FIG. 9). This increase is significantly different from the increase achieved by cocaine and heroin alone (P> 0.05 and 0.001, respectively) and cocaine / heroin conjugate (P> 0.001). The data obtained after pretreatment with GVG is not synergistic but similar to the additive effects of both cocaine (380%) and heroin (70%).

GVG abolishes the synergistic effect of the two drugs on the absolute grade of the increase and does not result in a transient response. After GV administration and subsequent cocaine / heroin administration, the NACC DA reached its maximum concentration within 180 minutes, which is the same as the response measured in animals that did not receive GVG prior to administration of the drug.

The results of this example show that GVG effectively attenuates the synergistic increase of NACC DA produced by the administration of cocaine / heroin. From the identification of the present invention with the previous studies of the present inventors, it can be seen that GVG is effective in the treatment of abuse of polydrug.

The above examples demonstrate that a drug selectively targeting a GABA system can be beneficial in the treatment of an abuse drug such as a stimulant, narcotic analgesic, alcohol and nicotine or a combination thereof. More specifically, GVG-induced GABA-T inhibitors that increase brain extracellular GABA levels are effective drugs and new tools for the treatment of cocaine, nicotine, heroin, methamphetamine and ethanol intoxication.

While the present invention has been described in connection with what is presently considered to be preferred embodiments thereof, it is evident that many alternatives, embodiments, and modifications will be apparent to those skilled in the art without departing from the spirit of the invention. These additional changes and modifications are within the scope of the appended claims.

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Claims (79)

Use of gamma-vinyl GABA (GVG) for the manufacture of a medicament useful for altering the addiction-related behavior of said primate by administering to a primate that has been abused by an abuse drug in an amount sufficient to reduce, inhibit or eliminate an abuse- . 3. The use according to claim 1, wherein the elimination of the behavior associated with the abuse drug craving occurs without a repulsive or desire response to GVG. 3. The use according to claim 1, wherein the abuse drug is selected from the group consisting of cocaine, morphine and nicotine. 3. The use of claim 1, wherein the medicament contains from about 100 mg / kg to about 300 mg / kg GVG. 4. The use of claim 1, wherein the medicament comprises from about 150 mg / kg to about 300 mg / kg of GVG. 4. The use according to claim 1, wherein the addiction related behavior is a conditioned place preference. Wherein said drug is administered to a primate that is abusive drug addictive in an amount sufficient to attenuate the compensating / stimulating effect of the drug of abuse selected from the group consisting of cocaine, morphine and nicotine without altering the compensating / stimulating effect of the food in the primate, The use of gamma-vinyl GABA (GVG) for the manufacture of a medicament useful for altering the relevant behavior. 8. The use according to claim 7, wherein the compensatory / stimulating effect of the abuse drug is attenuated without changing the motility activity of the primate. Use of gamma-vinyl GABA (GVG) for the manufacture of a medicament useful for ameliorating the nicotine poisoning effect of said primate by administering to a primate in an amount sufficient to reduce nicotine-dependent characteristics. 10. The use according to claim 9, wherein the medicament contains from about 75 mg / kg to about 150 mg / kg GVG. 10. The use according to claim 9, wherein the medicament contains from about 18 mg / kg to about 20 mg / kg GVG. 10. The use according to claim 9, wherein said nicotine dependent properties are reduced without a repulsion or desire response to GVG. 10. The use according to claim 9, wherein the nicotine dependent property is reduced without altering the athletic activity of the primate. (GVG) for the manufacture of a medicament useful for altering the addiction-related behavior of said mammal by administering to a mammal suffering from an abuse drug addiction in an amount sufficient to reduce, inhibit or eliminate the behavior associated with an abuse drug craving, Use of. 15. The use of claim 14, wherein elimination of the behavior associated with the abuse drug addiction occurs without a repulsive or desire response to GVG. 15. The use of claim 14, wherein the abuse drug is selected from the group consisting of an agonist, a narcotic analgesic, an alcohol or nicotine, and combinations thereof. 15. The use according to claim 14, wherein the abuse drug is selected from the group consisting of cocaine, nicotine, methamphetamine, ethanol, morphine, heroin and combinations thereof. 15. The use of claim 14, wherein said GVG is administered in an amount of about 15 mg / kg to about 600 mg / kg. 15. The use of claim 14, wherein the addiction-related behavior is a conditional site selection. An amount of an addictive drug addiction in an amount effective to attenuate the compensating / stimulating effect of an abuse drug selected from the group consisting of a stimulant, a narcotic analgesic, an alcohol, a nicotine, and combinations thereof without altering the compensation / Use of gamma-vinyl GABA (GVG) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for altering the addiction-related behavior of said mammal by administration to a mammal afflicted with said disease. 21. The use of claim 20, wherein the compensating / stimulating effect of the abuse drug is attenuated without altering the motor activity of the mammal. A medicament useful for improving the addictive agent, the narcotic analgesic agent, the alcohol or the nicotine poisoning effect of the mammal by administering to the mammal suffering from the addictive drug poisoning in an effective amount sufficient to reduce the stimulant, narcotic analgesic agent, alcohol or nicotine dependence characteristic Gt; GABA &lt; / RTI &gt; (GVG) or a pharmaceutically acceptable salt thereof. 23. The use of claim 22, wherein the GVG is administered in an amount of about 15 mg / kg to about 600 mg / kg. 23. The use according to claim 22, wherein said stimulant, narcotic analgesic, alcohol or nicotine dependent properties are reduced without a repulsive or desire response to GVG. 23. The use according to claim 22, wherein said stimulant, narcotic analgesic, alcohol or nicotine dependent properties are reduced without altering the motor activity of said mammal. (GVG) for the manufacture of a medicament useful for altering the addiction-related behavior of said mammal by administering to a mammal suffering from an abuse drug addiction in an effective amount sufficient to reduce, inhibit or eliminate the behavior associated with abuse drug craving, , Or a pharmaceutically acceptable salt, enantiomer or racemic mixture thereof. 27. The use of claim 26, wherein elimination of the behavior associated with the abuse drug addiction occurs without a repulsive or desire response to GVG. 27. The use according to claim 26, wherein the abuse drug is selected from the group consisting of an agonist, a narcotic analgesic, an alcohol or nicotine, and combinations thereof. 27. The use according to claim 26, wherein the abuse drug is selected from the group consisting of cocaine, nicotine, metamphetamine, ethanol, morphine, heroin and combinations thereof. 27. The use of claim 26, wherein said GVG is administered in an amount from about 15 mg / kg to about 600 mg / kg. 27. The use of claim 26, wherein said addiction related behavior is a conditional place selection. An amount of an addictive drug addiction in an amount effective to attenuate the compensating / stimulating effect of an abuse drug selected from the group consisting of a stimulant, a narcotic analgesic, an alcohol, a nicotine, and combinations thereof without altering the compensation / Use of gamma-vinyl GABA (GVG) or a pharmaceutically acceptable salt, enanthiomer or racemic mixture thereof for the manufacture of a medicament useful for altering the addiction-related behavior of said mammal by administration to a mammal afflicted with said disease. 33. The use of claim 32, wherein the compensating / stimulating effect of the abuse drug is attenuated without altering the motor activity of the mammal. A medicament useful for improving the addictive agent, the narcotic analgesic agent, the alcohol or the nicotine poisoning effect of the mammal by administering to the mammal suffering from the addictive drug poisoning in an effective amount sufficient to reduce the stimulant, narcotic analgesic agent, alcohol or nicotine dependence characteristic Gt; (GVG) &lt; / RTI &gt; or a pharmaceutically acceptable salt, enanthiomer or racemic mixture thereof. 35. The use of claim 34 wherein said GVG is administered in an amount from about 15 mg / kg to about 600 mg / kg. 35. The use according to claim 34, wherein said stimulant, narcotic analgesic, alcohol or nicotine dependent properties are reduced without a repulsive or desire response to GVG. 39. The use according to claim 38, wherein said stimulant, narcotic analgesic, alcohol or nicotine dependent properties are reduced without altering the motor activity of said mammal. The use of a composition for increasing the level of GABA in the central nervous system comprises administering to the mammal an effective amount sufficient to reduce, inhibit or eliminate the behavior associated with an abuse drug cravings or use, whereby the addictive- Use of the composition for the manufacture of a medicament useful for altering. 39. The composition of claim 38, wherein the medicament is selected from the group consisting of GVG, gabapentin, valproic acid, progabide, gamma-hydroxybutyric acid, fenugin, cetyl GABA, topiramate, thiabbin, A salt, an enantiomer or a racemic mixture. 39. The use of claim 38, wherein the ablation of an abuse drug addiction-related behavior occurs without a repulsive or desire response to GVG. 39. The use of claim 38, wherein the abuse drug is selected from the group consisting of an agonist, a narcotic analgesic, an alcohol or nicotine, and combinations thereof. 39. The use according to claim 38, wherein the abuse drug is selected from the group consisting of cocaine, nicotine, methamphetamine, ethanol, morphine, heroin and combinations thereof. 39. The use of claim 38, wherein said addiction related behavior is a conditional site selection. 39. The use of claim 38, wherein said medicament comprises gabapentin administered in an amount of from about 500 mg to about 2 g per day. 39. The use of claim 38, wherein the medicament comprises valproic acid administered in an amount from about 5 mg / kg to about 100 mg / kg per day. 39. The use of claim 38, wherein the medicament comprises topiramate administered in an amount of from about 50 mg to about 1 g per day. 39. The use of claim 38, wherein the medicament comprises pro-bead administered in an amount of from about 250 mg to about 2 g per day. 39. The use of claim 38, wherein said medicament comprises penghavin administered in an amount of about 250 mg to about 4 g per day. 39. The use of claim 38, wherein said medicament comprises gamma-hydroxybutyric acid administered in an amount of about 5 mg / kg to about 100 mg / kg per day. An amount of an addictive drug addiction in an amount effective to attenuate the compensating / stimulating effect of an abuse drug selected from the group consisting of a stimulant, a narcotic analgesic, an alcohol, a nicotine, and combinations thereof without altering the compensation / For the manufacture of a medicament useful for alleviating the addiction-related behavior of said mammal by administering to a mammal afflicted with said GABA. 53. The method of claim 50, wherein the agent is selected from the group consisting of GVG, gabapentin, valproic acid, progabide, gamma-hydroxybutyric acid, penbagin, cetyl GABA, topiramate, thiabbin, A salt, an enantiomer or a racemic mixture. 51. The use of claim 50, wherein the compensating / stimulating effect of the abuse drug is attenuated without altering the motor function of the mammal. A medicament useful for improving the addictive agent, the narcotic analgesic agent, the alcohol or the nicotine poisoning effect of the mammal by administering to the mammal suffering from the addictive drug poisoning in an effective amount sufficient to reduce the stimulant, narcotic analgesic agent, alcohol or nicotine dependence characteristic &Lt; / RTI &gt; the use of a composition to increase GABA levels in the central nervous system. 55. The method of claim 53, wherein said agent is selected from the group consisting of GVG, gabapentin, valproic acid, progabide, gamma-hydroxybutyric acid, fenugin, cetyl GABA, topiramate, thiabbin, A salt, an enantiomer or a racemic mixture. 55. The use of claim 53, wherein said medicament comprises gabapentin administered in an amount of from about 500 mg to about 2 g per day. 55. The use of claim 53, wherein said medicament comprises valproic acid administered in an amount of from about 5 mg / kg to about 100 mg / kg per day. 55. The use of claim 53, wherein said medicament comprises topiramate administered in an amount of from about 50 mg to about 1 g per day. 54. The use of claim 53, wherein said medicament comprises pro-bead administered in an amount of from about 250 mg to about 2 g per day. 54. The use of claim 53, wherein said medicament comprises penghavin administered in an amount of from about 250 mg to about 4 g per day. 54. The use of claim 53, wherein said medicament comprises gamma-hydroxybutyric acid administered in an amount of about 5 mg / kg to about 100 mg / kg per day. 54. The use of claim 53, wherein said stimulant, narcotic analgesic, alcohol or nicotine dependent properties are reduced without a repulsive or desire response to said medicament. 57. The use of claim 53, wherein said stimulant, narcotic analgesic, alcohol or nicotine dependent properties are reduced without altering the motor function of said mammal. For the manufacture of a medicament useful for altering the addiction-related behavior of said mammal by administering to said mammal suffering from the addiction of said abuse drug combination an effective amount sufficient to reduce, inhibit or eliminate the behavior associated with the craving of the combination of abusable drugs Use of gamma-vinyl GABA (GVG), or a pharmaceutically acceptable salt, enantiomer or racemic mixture thereof. 63. The use of claim 63, wherein elimination of the addiction-related behavior of said abuse drug combination occurs without a repulsive or desire response to GVG. 66. The use of claim 63, wherein said combination is selected from the group consisting of an agonist, a narcotic analgesic, an alcohol and nicotine. 66. The use of claim 63, wherein said combination is selected from the group consisting of cocaine, nicotine, metamphetamine, ethanol, morphine and heroin. 66. The use of claim 63, wherein said combination is cocaine and heroin. 65. The use of claim 63, wherein said GVG is administered in an amount from about 15 mg / kg to about 600 mg / kg. 65. The use of claim 63, wherein said addiction-related behavior is a conditional site selection. The present invention relates to the use of an abuse drug combination in an amount effective to attenuate the compensating / irritating effect of an abuse drug combination selected from the group consisting of an agonist, a narcotic analgesic, an alcohol and nicotine without altering the compensation / Use of gamma-vinyl GABA (GVG), or a pharmaceutically acceptable salt, enanthiomer or racemic mixture thereof, for the manufacture of a medicament useful for altering the addiction-related behavior of said mammal by administration to a hung mammal. 71. The use of claim 70, wherein said combination is selected from the group consisting of cocaine, nicotine, metamphetamine, ethanol, morphine and heroin. 71. The use of claim 70 wherein said combination is cocaine and heroin. 70. The use of claim 70, wherein the compensating / stimulating effect of the abuse drug combination is attenuated without altering the motor action of the mammal. Or a pharmaceutically acceptable salt thereof, is administered to a mammal suffering from the above-mentioned abuse drug combination poisoning in an amount sufficient to reduce the dependence properties on the combination of the abuse drugs selected from the group consisting of agonists, narcotic analgesics, alcohol and nicotine, Use of gamma-vinyl GABA (GVG), or a pharmaceutically acceptable salt, enanthiomer or racemic mixture thereof, for the manufacture of a medicament useful for improving the poisoning effect on a drug combination. 74. The use of claim 74, wherein the combination is selected from the group consisting of cocaine, nicotine, metamphetamine, ethanol, morphine and heroin. 74. The use of claim 74, wherein said combination is cocaine and heroin. 74. The use of claim 74, wherein said GVG is administered in an amount from about 15 mg / kg to about 600 mg / kg. 74. The use of claim 74, wherein said dependent property is reduced without a repulsion or desire response to GVG. 74. The use of claim 74, wherein said dependent property is reduced without altering the motor function of said mammal.