title: Long-lasting increase of alcohol relapse by the cannabinoid receptor agonist WIN 55,212-2 during alcohol deprivation.
abstract: Alcoholism is characterized by successive relapses. Recent data have shown a cross-talk between the cannabinoid system and ethanol. In this study, male Wistar rats with a limited (30 min sessions), intermittent, and extended background of alcohol operant self-administration were used. The relapse to alcohol after 1 week of alcohol deprivation was evaluated. Two weeks later, the animals were treated with the cannabinoid agonist WIN 55,212-2 (R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) (0, 0.4, 2.0, and 10.0 mg/kg, s.c.) during a similar alcohol deprivation period, and alcohol relapse during 2 weeks was assessed. A conditioned place preference (CPP) paradigm was used to study the rewarding properties of the cannabinoid agonist. Locomotor activity was also recorded. All doses of WIN 55,212-2 produced aversion in the CPP paradigm. The doses of 2.0 and 10.0 mg/kg resulted in an important suppression of spontaneous locomotor activity and a progressive weight loss during the next 2 weeks. The single alcohol deprivation was followed by a transient increase in their responding for alcohol from a range of 20-24 lever presses at baseline to a range of 38-48 responses in the first and second days (alcohol deprivation effect). However, the administration of WIN 55,212-2 during ethanol deprivation produced similar increased responses for alcohol but in a long-term way (at least over 2 weeks). These findings suggest that noncontingent chronic exposure to cannabinoids during alcohol deprivation can potentiate the relapse into alcohol use, indicating that functional changes in the cannabinoid brain receptor may play a key role in ethanol relapse.
authors.affiliation: Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid, E-28223 Madrid, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: López-Moreno
authors.forename: Gustavo
authors.initials: G
authors.lastname: González-Cuevas
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.forename: Miguel
authors.initials: M
authors.lastname: Navarro
mesh_terms: D000437:Alcoholism / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D048588:Benzoxazines; D001835:Body Weight / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D012646:Self Administration; D013037:Spatial Behavior / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013995:Time
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D000431:Ethanol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone