title: Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats.
abstract: The endocannabinoid system is involved in a variety of effects of drugs of misuse, and blockade of the cannabinoid CB1 receptor by selective antagonists elicits marked reductions in opioid and alcohol self-administration. The present study was designed to extend our knowledge of the role of the cannabinoid CB1 receptor in the modulation of alcohol misuse vulnerability in rats. Accordingly, using nonselected Wistar rats and genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, we investigated the effect of the CB1 antagonist SR141716A on operant alcohol self-administration and on reinstatement of alcohol-seeking behavior by environmental conditioning factors. In addition, in situ hybridization studies in both strains were performed to measure cannabinoid CB1 receptor mRNA in different brain areas of these animals. Results showed that intraperitoneal administration of SR141716A (0.03, 1.0 and 3.0 mg/kg) markedly inhibits ethanol self-administration and conditioned reinstatement of ethanol-seeking behavior in both strains of rats. ED50 analysis showed significantly higher sensitivity (P < 0.05) to the effect of SR141716A in msP rats than in heterogeneous Wistar rats. In situ hybridization studies revealed that, compared with Wistar rats, msP animals have consistently greater cannabinoid CB1 receptor mRNA expression in a number of brain areas, including the frontoparietal cortex, caudate-putamen and hippocampus (CA1 and dentate gyrus areas). In conclusion, we provide clear evidence that blockade of CB1 receptors reduces both ethanol self-administration and conditioned reinstatement of alcohol-seeking behavior in rats. In addition, current pharmacological and neuroanatomical data suggest that an altered function of the CB1 receptor system exists between genetically selected alcohol-preferring msP rats and a heterogeneous animal population.
authors.affiliation: Fundación Hospital Carlos Haya, Avenida Carlos Haya 82, 7 Planta, Pabellón A, 29010 Malaga, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cippitelli
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
authors.forename: Anita C
authors.initials: AC
authors.lastname: Hansson
authors.forename: Ignacio
authors.initials: I
authors.lastname: del Arco
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sommer
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.forename: Mauricio
authors.initials: M
authors.lastname: Massi
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Bermúdez-Silva
authors.forename: Miguel
authors.initials: M
authors.lastname: Navarro
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
authors.forename: Fernando Rodríguez
authors.initials: FR
authors.lastname: de Fonseca
mesh_terms: D000437:Alcoholism / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D005502:Food; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012054:Reinforcement, Psychology; D000077285:Rimonabant; D012646:Self Administration
chemical_list: D002492:Central Nervous System Depressants; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000431:Ethanol; D000077285:Rimonabant