Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention relates to the field of the necessities of life and, more particularly, the field of therapeutics.
• compositions intended to help the return to abstinence in a powerful way, the habitués of the drugs causing habituation and, thus, to get them to find a social and / or professional activity normal.
• Addiction or addiction
• Addiction can be defined as a behavioral disorder, characterized by a compulsive search for the product that causes this dependence, despite the adverse consequences for health, family life, work, etc., of which it is perfectly conscious the dependent person.
• This dependence is due to the excessive and repeated stimulation of the opioid receptors, in particular of the mu type (Matthes et al., Nature Nature, 1996,383,819-823), more particularly in the cerebral structures forming the limbic system (ventral tegmental area, nucleus accumbens , amygdala, prefrontal cortex, etc.). It gradually follows changes in the functioning of the neurons that maintain this state of dependence and, above all, cause a very powerful and very long-lasting remanence of the effects of the substance.
• the opioid substances, dopaminergic agonists, as may be methadone or buprenorphine act on the same receptors and in the same sense as those on which the narcotic drugs act.
• the compositions according to the invention act rather in the manner of Naloxone.
• the present invention should find a therapeutic application starting from the modulation of the concerned receptors and a particular kinetic and potential stimulation, and not of an antagonistic action.
• the invention described in US 2005 / 01476Al is not precisely a treatment of addiction but should be considered as a broader psychiatric treatment ranging from schizophrenia to anxiety, in the middle of which could find a place the treatment of addiction, since the use of cannabis is a major problem in this area.
• the lack of specificity allows the description of any psychotropic substance as a potential treatment for addiction but the specificity is largely unproven after the agonist (blocking agent) action of the molecule and the drug responsible for the abuse.
• the references of the prior art mainly treat the symptomatic signs of the disease and this is what the authors of the previous references (US 2005/171110) confirm: the modulators of the cannabinoid receptors can reduce or improve the 'abuse of a substance or disorders by addiction. Therefore, a combination of cannabinoid receptor modulators with drugs used to treat addictive disorders may result in dose reduction or improving the effectiveness of common addiction-related disorders.
• the present invention is therefore a specific combination of treatments which will eventually be used for various psychiatric applications but which are mainly intended for the treatment of addiction. This does not mean that the various compounds of the invention could be added to other drugs already used, but that the specific combination of these two molecules will operate better than either, taken alone on a population of patients who can not be defined beforehand as psychotic or by another known diagnosis.
• the result of this invention is to modify the current maintenance regimens in contrast to the others for which the doses increase so long until sedation occurs.
• the principle of the present treatment consists in setting up a second molecule which essentially provides the maintenance treatments with the lowest possible but necessary dosage.
• the present invention makes it clear that a double action on a given dopaminergic system can treat drug addicts who respond to a diagnosis of psychosis.
• the present invention draws its effectiveness from simultaneous actions, direct and indirect, which has the effect precisely an action on dopaminergic neurons.
• WO2004 / 100992 describes a novel element aimed at improving antipsychotic treatments of the "new generation" type, such as, for example, a treatment with a conventional antipsychotic to which the authors of this reference add either benzodiazepines or GABAergic modulators.
• the reference WO2005 / 181071 describes an innovation aimed at obtaining an improvement in the treatment of depression in which depressions resistant to conventional treatments result from a new hypothesis concerning the transmission of monoamines.
• This reference describes neither the treatment of addicts nor the treatment of addiction but describes an improvement in the treatment of psychosis.
• the inventor relies either on the dopaminergic antagonist combination + SSRI (Selective Serotonin Reuptake Inhibitor) or on mood regulators + SSRI.
• the therapeutic principle combines an agonist and an antagonist even though there is absolutely no description of such a principle.
• neither of the two active ingredients is a direct agonist of the dopaminergic system.
• the authors use one of two indirect agonists (SSRI) which is a very slow or even delayed dopaminergic agonist. This contributes to distorting and definitively differentiating this system from that which is the subject of the present patent application.
• SSRI indirect agonists
• buprenorphine nor methadone are listed as dopaminergic agonists in the supposedly exhaustive list of dopamine agonist molecules, provided in US2005 / 181071.
• the present invention does not relate to an effect on the cannabinoid receptors (CB1 and CB2).
• the present invention does not relate to two opposite actions (agonists or antagonists) but essentially mainly two simultaneous agonist actions. This must result in stable dopaminergic action brought about by these simultaneous actions.
• a combination of direct and indirect activators is used.
• a "direct action” means an action according to which an administered molecule will directly activate a reaction on dopaminergic neurons which may be of inhibition or stimulation.
• An “indirect action” means that one activates neuromodulators that go secondarily (or consequently) to stimulate the dopaminergic neurons.
• the subject of the present invention is therefore a well-defined combination of treatments which may optionally be provided for psychiatric applications but which is particularly related to addiction phenomena. This does not mean that the molecules in question could be added to others already in use but claimed that the specific combination of two molecules will operate with a * more effectively than either alone in a population of patients that can not be previously defined as psychotic or for other known diagnoses.
• the object of the present invention is to modify the current therapies of substitution treatments (OST maintenance), which the others do not do: a usual principle consists in increasing the doses until sedation appears. According to the present technique, it is preferable to set up a second molecule so as to put the substitution treatments at their lowest possible but necessary dose level.
• OST maintenance substitution treatments
• the invention has been based on the principle that it is important to simultaneously implement two direct and indirect prodopaminergic molecules in dependent patients. This specific regulation will allow a gradual return to a neuronal situation closer to stability, helping to restore systems that have been deregulated by repeated use of compounds during the addiction period. That will be worth for opioid substitution treatments, but also for supplements.
• the invention which is the subject of the present patent application, lies in the fact that, against all odds, the treatment of persons dependent on heroin and opioids and also, to a lesser degree, on psycho-stimulants (cocaine for example ), by the combination of a dopaminergic receptor ligand with a prodopaminergic action (hereinafter referred to as direct prodopaminergic), in particular of the D2 and / or D3 type, and a second compound which can be described as dopaminergic, not acting directly on dopamine receptors but modulating dopamine release indirectly (opioid - including methadone, buprenorphine, LAM (Levo-alpha acetylmethadol)) or any other substances claimed to possess this property acting on opioid receptors ...) (later called pro-dopaminergic indirect), leads to a rapid improvement in the state of inner psychic tension that leads to research compulsive of the addictive substance.
• direct prodopaminergic a dopaminergic receptor ligand with
• the combination when administering the two substances (a direct pro-dopaminergic and an indirect pro-dopaminergic) is capable of producing an anti-addiction effect, at least during the first weeks of treatment.
• the improvement of the physical state of the dependent persons is such as to allow to establish very quickly a research of the root causes of the compulsive behavior, characteristic of the addiction.
• the invention therefore specifically relates to a pharmaceutical composition containing a combination of two drugs, preferably in the form of a kit, intended to be administered, simultaneously or successively, to facilitate weaning, which consists of a combination of two agonists: the a direct prodopaminergic especially D1, D2 and D3 receptors, and the other is an indirect pro-dopaminergic (capable of modulating dopamine release), including opioid-substituted products, in the form of a pharmaceutical composition for parenteral or transdermal oral administration.
• the dopaminergic agonist is preferably a D1, D2, or D2 / D3 agonist.
• the indirect pro-dopaminergic agonist may be defined as a substance which may or may not be attached to or on opioid receptors, which exhibits only weakly euphoric activity and / or which exhibits only a limited effect of addiction.
• methadone, buprenorphine, the product called LAM, nalorphine, naltrexate, Levallorphan, and, in general, any substance described as having such a property may be mentioned. It can also be cocaethylene.
• the invention therefore lies in the fact of administering such a combination either simultaneously in the form of a defined single pharmaceutical composition, or in the form of a kit containing each of said active ingredients in a separate form which can thus be administered to variable dosages, or at different rates or in a different order, or in different forms.
• the concentrations of active ingredients may also vary, from a strong dosage to a lower dosage, depending on the therapeutic needs, the continuation of treatment and the occurrence of side effects.
• Amisulpride or its salts and, in particular, S (-) Amisulpride for the treatment of affective or cognitive symptoms of schizophrenia, for the treatment of autism, or the treatment of tardive dyskinesias are already known. caused by neuroleptics (PCT / EP99 / 05325). Patent PCT / EP99 / 05325 also mentions that S (-) Amisulpride can be used against "Drug Addiction" without further specification.
• Amisulpride is one of many representatives of the benzamide series described in US Patent 4,401,822 as an anti-apomorphine substance.
• the synthesis of amisulpride in racemic or enantiomerically pure form [S (-)] is described in application PCT / EP99 / 05325, as well as that of its salts.
• Amisulpride is described in pharmacology as displacing [ 3 H] racloprid of limbic D2 receptors. Amisulpride, because of its central action, can be considered an antipsychotic drug in subjects with schizophrenia, especially with fewer side effects than known anti-psychotic neuroleptic drugs, such as extrapyramidal syndrome, etc. .
• Amisulpride is therefore a known medicine, but until now used in other neuro-psychiatric indications.
• the doses administered in the context of the pharmaceutical compositions according to the invention will vary according to the effect
• the effect of the drugs, object of the present association is manifested quickly and already in preclinical studies, a positive effect is noted taking into account the effect of impregnation.
• the doses administered in the context of the pharmaceutical compositions according to the invention will vary according to the desired effect, the age of the addictive drug addiction and the intensity of the action against the desired addiction.
• Doses of direct pro-dopaminergic substances may vary from 1 mg to 600 mg per unit dose.
• Doses of the indirect pro-dopaminergic compound will vary from 0.2 mg to 2000 mg per unit dose, preferably from 0.2 mg to 300 mg per unit dose.
• the combination will be composed of direct prodopaminergic compound tablets, containing from 25 mg to 500 mg of active ingredient, and tablets of indirect prodopaminergic substance, at a dose of 0.2 mg at 500 mg per unit dose.
• the direct prodopaminergic compound is preferentially Amisulpride.
• the indirect prodopaminergic substance is preferably selected from methadone, buprenorphine, the product called LAM 3 , nalorphine, naltrexate, Levallorphan and cocaethylene.
• kits containing for example two vials of a solid or liquid preparation, one of the vials containing a solution of direct prodopaminergic substance, the other vial containing a solution. or a suspension of indirect prodopaminergic substance, such as, for example, an aqueous syrup or suspension of methadone.
• Injectable forms can also be made.
• Transdermal forms may also be contemplated with a prolonged effect.
• the usual dosing regimen usually consists of using low doses of prodopaminergic drug and then gradually increasing doses to achieve a "plateau" effect.
• the daily dosage will range from 50 to 500 mg, and from 50 to 400 mg.
• the dosage will range from 1 to 4 mg per day.
• the order of administration of the two components of the combination according to the invention is not critical and can be modulated according to the needs of the therapy. It would seem preferable to ensure the administration in the first place of the substance prodopaminergic indirect, then direct prodopaminergic product. It is possible, on the contrary, to administer in the first place the direct prodopaminergic product then followed by the administration of the indirect prodopaminergic product. In any case, it is more convenient that the administration of the two active ingredients is simultaneous.
• the subject of the invention is also a pharmaceutical composition consisting of a combination of a direct prodopaminergic product or of a salt thereof, and of an indirect prodopaminergic product or of a salt thereof, containing, for example, from 50 to 500 mg of Amisulpride and 0.2 to 30 mg of indirect prodopaminergic product in an inert, non-toxic, pharmaceutically acceptable carrier or vehicle.
• the dosage is modulated by increasing first, then when the threshold effect is reached, the dosage of one and / or the other prodopaminergic products is decreased.
• the indirect prodopaminergic product is chosen from naltrexone, nalorphine and buprenorphine, preferentially buprenorphine.
• Another object of the invention resides in the production of a kit containing a first pharmaceutically appropriate dosage of direct dopaminergic substance such as amisulpride in base form or in salt form, in racemic form or in enantiomeric form, with the dose of 100 to 400 mg and a second pharmaceutically appropriate dosage of methadone containing 5 to 200 mg methadone per unit dose.
• a first pharmaceutically appropriate dosage of direct dopaminergic substance such as amisulpride in base form or in salt form, in racemic form or in enantiomeric form
• Another object of the invention resides in the production of pharmaceutical compositions consisting of a combination of Risperidone and an indirect pro-dopaminergic chosen from nalorphine, methadone, buprenorphine and nallorphan, such that the dose of Risperidone is from 1 to 4 mg per unit dose.
• the invention also relates to an anti-addiction drug consisting of the combination of sulpiride in racemic or optically active form, free or salified by a mineral or organic acid, and buprenorphine.
• the pharmaceutical compositions may further contain a neuroleptic such as a phenothiazine.
• the combination according to the invention is intended to be administered once or twice a day, exceptionally three times a day, to ensure a constant impregnation of the subject in medicine.
• the invention further relates to a method for combating various forms of habituation to licit or illicit drugs by administering to subjects who are addicted to licit or illicit drugs a sufficient and effective amount of an association of one or more drugs.
• direct dopamine agonist and an indirect prodoparninergic agonist simultaneously, in a single or separate pharmaceutical form, or in batch form, by first administering the indirect prodoparinergic compound, in a given pharmaceutical form, and then the direct dopaminergic agonist under a other pharmaceutical form, for example in kit form.
• the method described above is particularly suitable for combating addiction to opiate drugs, such as heroin. It is also used in the fight against the use or abuse of active ingredients that are addictive, such as, for example, amphetamine and its derivatives, alcohol, cocaine, cannabis, and MDMA.
• opioid receptors make it possible to obtain a large number of physiological and pharmacological responses. Indeed, the opioid system is involved in the modulation of stress, pain, mood, cardiovascular function, and food intake (Vaccarino et al., 2000).
• radiolabeled ligands with high specific activity has led to the discovery in the central nervous system of mammals, stereospecific, saturable and high affinity receptors. These membrane binding sites specific for exogenous opiates were identified by three teams (Simon et al., 1973, Terenius 1973, Pert and Snyder 1973). More recently, receptors have been cloned and are defined as being of three types: ⁇ , ⁇ , and K (Kieffer et al, 1992, Chen et al., 1993, Yasuda et al, 1993).
• opioid receptors belong to Ia family of receptors with seven transmembrane domains linking heterotrimeric G proteins (Dohlman et al., 1987). These receptors have a sequence homolog of 60% in humans, the most conserved sequences being the transmembrane domains and intracellular loops. In addition, they are distributed differently in the central nervous system. ⁇ opioid receptors are
• the delta and kappa receptors have a smaller distribution, they are mainly present in the ventral and dorsal striatum for the first, and the dorsal striatum and the preoptic area for the second (Mansour et al., 1988).
• opioid receptors inhibit adenylate cyclase activity (Sharma et al., 1977), leading to a decrease in intracellular cAMP levels, decreasing calcium conductance (Hescheler et al., 1987, Surprenant et al., 1990). ), stimulate the potassium channels (North et al., 1987) and increase intracellular calcium levels (Jin et al., 1992). More recently, it has been shown that these receptors are capable of generating mitogenic signals by activating the MAP kinase pathway (Fukada et al., 1996).
• the endogenous ligands of the opioid receptors are the endomorphins (Hughes et al., 1975). They are neuropeptides released into the synaptic space, from large dense-heart vesicles, as a result of stimulation of neurons where they coexist with other neurotransmitters. Endomorphins derive from distinct precursors and are heterogeneously present in the different neuronal populations of the central nervous system.
• Proopiomelanocortin (or POMC) gives rise to ⁇ -endorphin and related peptides
• pro-enkephalin A is responsible for enkephalins (Met- and Leu-enkephalin) and related peptides
• prodynorphin gives rise to neo- endorphins and dynorphin (Akil et al., 1998).
• Enkephalins have a very short lifespan after their release (less than a minute). This brevity is not due, as for most classical neuromediators, to a recapture system but to their enzymatic degradation. Met-enkephalin (Try-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-GIy-Gly-Phe-Leu) are rapidly hydrolysed by cleavage of the Gly-Phe bond by a peptidase initially called peptidase initially called enkephalinase, which has since been shown to be identical to neutral endopeptidase (NEP), and at the Tyr-Gly linkage by raminopeptidase N (APN) (Roques, 1986). These two enzymes belong to the same group of zinc metallopeptidases.
• Inhibitors of enkephalin catabolism increase the extracellular concentration of enkephalins without affecting their release (Daugé et al., 1996, Bourgoin et al., 1986, Waksman et al., 1985).
• the advantage of these molecules is that, even at very high doses, they never induce pharmacological responses as powerful as morphine (Ruiz-Gayo et al., 1992, Abbadie et al., 1994), and are therefore lacking the classic side effects of opioids (constipation, dry mouth, itching, irregular periods, and at a more serious level, gastrointestinal disorders and respiratory depression).
• opioids Constipation, dry mouth, itching, irregular periods, and at a more serious level, gastrointestinal disorders and respiratory depression.
• the oldest known opioid receptor ligand used in medicine is morphine, an alkaloid derived from the Indian poppy.
• Heroin diacetylmorphine, diamorphine
• diamorphine diamorphine
• this substance is very popular with drug addicts, because of its rapid penetration into the brain where it generates an answer called orgasmic, the "high”.
• opioid agonists are nowadays used in substitution treatments, such as methadone and buprenorphine.
• Methadone is a synthetic opioid and, like morphine, is a preferred ⁇ receptor agonist.
• opioid antagonists are conventionally used as selective ligands, respectively of ⁇ and ⁇ receptors in experimental pharmacology.
• opioid antagonists Another class of exogenous ligands for opioid receptors exists: opioid antagonists.
• naloxone is used therapeutically in the treatment of acute opioid poisoning. This molecule binds with the same affinity to both ⁇ and ⁇ receptors.
• Another known antagonist is naltrindole, which binds with a very high affinity to ⁇ receptors (Fang et al., 1994). It is widely used in experimental pharmacology.
• addiction / addiction is a syndrome in which the consumption of a product becomes a higher requirement than other behaviors previously of maximum importance.
• Dependency settles with the repetition of drug taking and is characterized by a compelling need for the drug that leads to its compulsive search.
• Dependence has two facets: physical and psychic. The physical component requires the addict to consume drugs or pain specific to the withdrawal syndrome (which, except exceptional case, is not fatal despite the strength of pain). It may disappear after a few days.
• the psychic component is the desire of the addict to start again, it is associated with strong stimulation of the brain by the reinforcement / reward system and is the cause of many relapses in drug addiction. It can last several years.
• Tolerance is the process of adapting an organism to a substance, which results in the progressive weakening of its effects, and leads to the need to increase the dose to achieve the same effects. In animals, tolerance leads to a decrease in the behavioral effects induced by the drug following repeated administration.
• Opioid withdrawal is manifested inter alia by hypertension and abdominal cramps, but also by Panhedonia and dysphoria.
• opioid withdrawal may be caused by the administration of an opioid antagonist, naloxone.
• opioid antagonist naloxone
• Several behavioral changes are then observed in morphine-dependent rats: increased grooming, chewing, blinking, but also diarrhea or weight loss.
• the dopaminergic system is under the influence of many transmitters, inhibitors or activators. It has also been shown that many catecholaminergic, serotoninergic, glutamatergic, GABAergic, cholinergic and peptidergic systems undergo significant changes in opiate dependence (Nieto et al., 2002, Ammon-Treiber et al., 2005).
• mice no longer expressing the gene encoding the mu-type opioid receptor, no longer develop dependencies not only on opiates, but also on alcohol, cannabinoids, and cocaine (Becker et al., 2002, Matthes et al., 1996).
• mice no longer expressing the gene coding for the dopaminergic D2 receptor which are mice incapable of developing a palatability for morphine (Maldonado et al., 1997), express a very high rate high level of pre-proenkephalin, precursor of enkephalins (endogenous opioid peptides) (Baik et al., 1995).
• Dopamine acts on two classes of receptors: "Dl-like” and "D2-like".
• Dl-like receptors D1 and D5 are coupled via Gs to adenylate cyclase and allow the production of cAMP that triggers many protein kinase A dependent metabolic responses.
• D2-Iike receptors D2, D3 and D4 are coupled to Gi / o and inhibit the synthesis of cAMP, which facilitates in particular the opening of hyperpolarizing K + channels.
• Dopaminergic neurons are organized in cell groups, they are highly branched and innervate several structures of the brain.
• the two major dopaminergic groups located at the junction of midbrain and diencephalon are the mgro-striatal system (designated A8 and A9) and the mesocorticolimbic system (AlO group).
• the AS and A9 neurons originate in the dark substance (ventrolateral part of the mesencephalon) and project on the striatum. They play a vital role in the regulation of motor functions. The degeneration of these nigrostriatal neurons is responsible for Parkinson's disease (German et al., 1989).
• the cell bodies of the dopaminergic AlO neurons (DA-AlO) are located in the Ventral Tegmental Area (VTA) (Oades et al, 1987). They project on all the structures of the limbic system: the nucleus accumbens, the olfactory tubercles, the amygdala, the septum, the hippocampus and the frontal cortex.
• Dopamine neurons are mainly assembled in two mesencephalic nuclei.
• One is the tegmentum or ventral tegmental area (ATV, or mesencephalic area AIO) whose axonal projections innervate the cortex (especially in its anterior part), the limbic system (especially the septum and amygdala) and nuclei of the base (putamen and nucleus accumbens).
• ATV tegmentum or ventral tegmental area
• AIO mesencephalic area
• Most of these fibers pass through the medial telencephalic beam (FMT) and are involved in the processing of cognitive-affective information.
• FMT medial telencephalic beam
• this neural wiring belongs to the reward / reinforcement system that produces a very strong brain stimulation in order to experience pleasure (hedonic action) in behaviors essential to the survival of the species or the individual. It is this motivational circuit that is hijacked by drugs. Thus, these, by producing pleasure, motivate the individual towards a compulsive behavior where the drug use replaces the behaviors of survival.
• the other dopaminergic nucleus is the substantia nigra (substantia nigra or substantia nigra or mesencephalic area A9) that emits axons to the striatum (caudate nucleus and putamen) and participates in the control of locomotion. Drugs that alter the level of dopamine release in the striatum, upset motor skills.
• Amisulpride is a molecule chemically related to benzamides. At low doses, Amisulpride has an antagonistic effect on presynaptic D2 and D3 receptors
• mice Male OFl mice weighing about 20 g at the beginning of the experiments (Charles River, France). They live in an environment whose daily light cycle (7:30, 19:30) is constant throughout the year, and the temperature is maintained at around 22 ° C. Mice have free access to water and food, and experiments are conducted in accordance with the international rules of ethics of animal testing.
• mice are placed individually in a plastic cage (255 cm x 205 cm) isolated from the noise and are exposed to a light intensity of 5 lux.
• the movements of the animals are captured by photocells for 60 minutes and recorded by a computer.
• the experiment begins immediately after the injection of the product.
• locomotor activity only takes into account horizontal movements of animals.
• ANOVA One-way analysis of variance
• a molecule with a dopaminergic antagonist activity decreases locomotor activity. It is this property that is involved in order to determine the dose at which Amisulpride has a dopaminergic antagonist activity in mice (an effect on D2 and D3 postsynaptic receptors, and not on D2 auto-receptors and D3).
• the doses tested were: 0.5 mg / kg, 2 mg / kg, 1 mg / kg, 20 mg / kg and 50 mg / kg.
• locomotor activity is significant from 10 mg / kg.
• locomotor hyperactivity is observed at low dose (0.5 mg / kg). This dose resulting in pro-dopaminergic response is therefore chosen for the rest of the experiments.
• Amisulpride and buprenorphine combination can behavioral sensitization be reduced following morphine pretreatment
• AMS Amisulpride
• Bup 0.1 mg / kg 5
• the animals are treated for 6 days with cocaine (20 mg / kg i.p.).
• the locomotor activity of the animals is measured for 1h immediately after i.p. at J1, J3 and J6. Then, the animals were weaned for 6 days before re-injecting saline, cocaine (20 mg / kg ip) or cocaethylene (20 mg / kg ip), and again measuring the locomotor activity of the animals. Ih.
• Graph I shows the changes in locomotor activity of the animals at Day 11 after morphine injection at a dose of 10 mg / kg.
• the animals receive, from day 1 to day 7, either morphine or saline, from day 8 to day 4, or physiological saline, buprenorphine, isulpride, buprenorphine and amisulpride according to the scheme:
• Chart II shows the level of overall locomotor activity measured for one hour.
• the animals were treated for 6 days with cocaine (20 mg / kg ip) or saline. Then, the animals were weaned for 6 days before re-injecting cocaine (20 mg / kg ip) of cocaethylene (20 mg / kg ip) or saline. ** p ⁇ 0.01
• Opioids mobilize calcium from inositol 1,4,5-trisphosphate-sensitive stores in NG108-15 cells. JNeurosci. 1994 Apr; 14 (4): 1920-9. Johnson SW, North RA. Opioids excites dopamine neurons by hyperpolarization of local interneurons. J Neurosci. 1992 Feb; 12 (2): 483-8.
• Kieffer BL Befort K, Gaveriaux-Ruff C, Hirth CG.
• the delta-opioid receptor isolation of a cDNA by expression cloning and pharmacological characterization.
• Roques BP Fournie-Zaluski MC. Enkephalin degrading enzyme inhibitors: a physiological way to new analgesia and psychoactive agents. NIDA Res Monogr. 1986; 70: 128-54. Roques BP. Zinc metallopeptidases: active site structure and design of selective and mixed inhibitors: new approaches in the search for analgesia and antihypertensives. Biochern Soc Trans. 1993 Aug; 21 (Pt 3) (3): 678-85.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Emergency Medicine (AREA)
• Addiction (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Psychology (AREA)
• Anesthesiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=37054597

Family Applications (2)

Family Applications Before (1)

Country Status (7)

Families Citing this family (5)

Family Cites Families (10)

• 2006
  • 2006-02-17 WO PCT/FR2006/000372 patent/WO2007096489A1/fr active Application Filing
  • 2006-02-17 EP EP06725976A patent/EP1988883A1/de not_active Withdrawn
• 2007
  • 2007-02-19 EP EP07705612A patent/EP2015739A1/de not_active Withdrawn
  • 2007-02-19 CN CNA2007800136067A patent/CN101420944A/zh active Pending
  • 2007-02-19 JP JP2008554881A patent/JP2009526833A/ja not_active Withdrawn
  • 2007-02-19 US US12/278,622 patent/US20110039834A1/en not_active Abandoned
  • 2007-02-19 WO PCT/IB2007/000390 patent/WO2007093909A1/fr active Application Filing
  • 2007-02-19 CA CA002642561A patent/CA2642561A1/fr not_active Abandoned
  • 2007-02-19 AU AU2007216255A patent/AU2007216255A1/en not_active Abandoned

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events