title: The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence.
abstract: Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively) blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France) and cyproheptadine (1 mg/kg) could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs.
authors.affiliation: Key-Obs SAS, Orléans, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Trovero
authors.affiliation: Key-Obs SAS, Orléans, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: David
authors.affiliation: Greenpharma SAS, Orléans, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bernard
authors.affiliation: Service de pharmacologie, groupe hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Puech
authors.affiliation: Key-Obs SAS, Orléans, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Bizot
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130, Neuroscience Paris Seine, Paris, France.|Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience Paris Seine, Paris, France.
authors.forename: Jean-Pol
authors.initials: JP
authors.lastname: Tassin
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000437:Alcoholism / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003533:Cyproheptadine / Q000494:pharmacology / Q000627:therapeutic use; D000431:Ethanol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011224:Prazosin / Q000494:pharmacology / Q000627:therapeutic use; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D003533:Cyproheptadine; D000431:Ethanol; D000661:Amphetamine; C010739:ifenprodil; D011224:Prazosin