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• • 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 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, but also, to a lesser extent, on psycho-stimulants (cocaine by example), by the combination of a dopaminergic receptor ligand s with a prodopaminergic action (hereinafter referred to as direct prodopaminergic), in particular of the D2 and / or D3 type, and a second compound which may be described as pro-dopaminergic, not acting directly on dopamine receptors but modulating dopamine release indirectly (GABAergic, opioid - including methadone, buprenorphine, AML (Levo-alpha acetylmethadol)) or all other substances claimed to possess this property acting on opioid receptors ...) (hereinafter referred to as indirect pro-dopaminergic), leads to a rapid improvement in the state of inner psychic tension which leads to the compulsive search for the addictive substance.
• association during the administration of the two substances (a pro-dopaminergic direct and an indirect) is capable of producing an anti-addiction effect, at least during the first weeks of treatment.
• the improvement of the physical condition of dependent persons is such that it makes it possible very quickly to establish a search for the underlying causes of the compulsive behavior characteristic of 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 drug in particular D 1, D 2 and D 3 receptors, and the other an indirect pro-dopaminergic (capable of modulating dopamine release), including opioid-substituted products, in the form of a composition pharmaceutical form for parenteral or transdermal oral administration, but also valproic acid, the action of which on the GABAergic system indirectly modulates the levels of circulating dopamine.
• 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 drug in particular D 1, D 2 and D 3 receptors, and the other an indirect pro-dopamine
• the dopaminergic agonist is preferably a D1, D2, or D2 / D3 agonist.
• dopamine receptor antagonist substances but modulating the release of dopamine, such as sulpiride, metoclopramide or haloperidol may also be used.
• Indirect pro-dopaminergic can be defined as a substance that may or may not be attached to or on opioid receptors, which exhibits only weakly euphoric activity and / or exhibits only a limited addictive effect.
• 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. It may also be, in the indirect agonist, a molecule such as valproic acid or carbamazepine, acting on the GABAergic system.
• 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 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 the application
• Amisulpride is described in pharmacology as displacing [ 3 H] racloprid of limbic D2 receptors. Amisulpride, because of its central action, may be considered an antipsychotic drug in subjects with schizophrenia, especially with fewer side effects than known antipsychotic neuroleptic drugs, such as extrapyramidal syndrome, etc. .
• Amisulpride is therefore a known medicine, hitherto used in other neuropsychiatric indications.
• 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.
• Direct pro-dopaminergic doses may range from 1 mg to 1200 mg per unit dose.
• Doses of the indirect prodopaminergic compound will range from 0.3 mg to 2000 mg per unit dose.
• the combination will be tablets of direct prodopaminergic compound, such as amisulpride, containing from 50 mg to 500 mg of the principle active, and indirect prodopaminergic substance tablets such as buprenorphine, at a dose of 0.2 mg to 30 mg per unit dose.
• direct prodopaminergic compound such as amisulpride
• indirect prodopaminergic substance tablets such as buprenorphine
• 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 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 first administer the indirect prodopaminergic substance and then the 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 invention also relates to a pharmaceutical composition consisting of a combination of a direct prodopaminergic or a salt thereof, and buprenorphine, for example containing 50 to 500 mg amisulpride and 0.2 to 30 mg of buprenorphine in an inert, non-toxic, pharmaceutically acceptable excipient or vehicle by modulating the dosage, firstly by increasing and then when the threshold effect is reached, the dosage of one and / or the other is decreased. prodopaminergics.
• Another object of the invention is the production of a kit containing a first pharmaceutically appropriate dosage of direct dopaminergic substance in base form or in the form of salt, in racemic or enantiomeric form, at a dose of 100 to 400 mg and a second pharmaceutically appropriate dosage of methadone containing 5 to 60 mg methadone 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 neurolytic.
• 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 dopaminergic agonist and indirect prodopaminergic simultaneously, in a single or separate pharmaceutical form, or in batch form, by first administering the prodopaminergic compound indirect, in a given pharmaceutical form, then the direct dopaminergic agonist in another form pharmaceutical, 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).
• These receptors have a sequence homology of 60% in humans, the most conserved sequences being the transmembrane domains and the intracellular loops. In addition, they are distributed differently in the central nervous system. ⁇ opioid receptors are widely present in the entire central nervous system, with very high concentrations in some areas such as basal ganglia, limbic structures, thalamic nuclei and important regions for nociception. 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 have been extensively studied in different tissues, cell types or neuron preparations. These three receptors have been shown to be coupled to Gi / Go proteins that modulate many effectors. Indeed, opioid receptors inhibit adenylate cyclase activity (Sharma et al., 1977), resulting in decreased levels of intracellular cAMP, decrease calcium conductance (Hescheler et al., 1987, Surprenant et al, 1990). , stimulate 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-Gly-Gly-Phe-Leu) are rapidly hydrolysed by cleavage of the Gly-Phe bond by a peptidase initially called enkephalinase, which has since been shown to be identical to neutral endopeptidase (NEP), and at the Tyr-Gly linkage by aminopeptidase N (APN) (Roques, 1986). These two enzymes belong to the same group of zinc metallopeptidases.
• Inhibitors of catabolism of enkephalins increase the extracellular concentration of enkephalins without affecting their release (Dauge 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 now 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 ⁇ 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 a 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 anhedonia 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 pre-proenkephalin, precursor of enkephalins (endogenous opioid peptides) (Baik et al., 1995).
• 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-like 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 main dopaminergic groups located at the junction of midbrain and brain are the nigrostriatal system (designated A8 and A9) and the mesocorticolimbic system (AlO group).
• the A8 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 dopaminergic neurons AlO (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 AlO) 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
• AlO 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 participating in the control of locomotion. Drugs that alter the level of dopamine release in the striatum, upset motor skills.
• Morphine administration stimulates the activity of dopaminergic neurons in the substantia nigra and ATV, resulting in increased dopamine release in the caudate-putamen nucleus and the nucleus accumbens (Matthews and German, 1984; Spanagel et al., 1990, Di Chiara and North, 1992). It is commonly accepted that this increase is due to an indirect action of opioids. Indeed, activation of the ⁇ receptors present on the surface of GABAergic interneurons located in the cross-linked black substance and ATV would lead to the lifting of the inhibition exerted by these interneurons on dopaminergic neurons (Johnson and North, 1992, Bontempi and Sharp , 1997).
• 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 (7h30, 19h30) is constant throughout the year, and the temperature is maintained at around 22 0 C. The mice have free access to water and water. food, and the experiments are carried out in accordance with the international rules of ethics of animal experimentation.
• 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.
• a one-way analysis of variance (ANOVA) (treatment) is used for all behavioral tests performed, followed by a Student-Newman-Keuls test if p ⁇ 0.05 in P ANOVA. In all cases, significance is accepted when p ⁇ 0.05.
• a molecule with a dopaminergic antagonist activity decreases locomotor activity. It is this property that is involved in determining 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 are: 0.5 mg / kg, 2 mg / kg, 10 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 after morphine pretreatment
• AMS amisulpride
• Buprenorphine dose Bup: 0.1 mg / kg
• 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) on J13, and again measuring the locomotor activity of the animals during 1 hour. .
• 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 morphine or physiological saline from day 1 to day 14, or physiological saline, buprenorphine, amisulpride, 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. J Neurosci. 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. Proc Natl Acad Sci U S A. 1992 Dec 15; 89 (24): 12048-52. Erratum in: Proc Natl Acad Sci USA 1994 Feb 1; 91 (3): 1193. Maldonado R., A. Saiardi, O. Valverde, TA Samad, BP Roques and E. Borrelli, Absence of opiate rewarding effects in mice lacking dopamine D2 receptors, Nature 1997, 388: 586-9
• 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. Biochem Soc Trans. 1993 Aug; 21 (Pt 3) (3): 678-85.

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