title: Cannabinoid receptor stimulation increases motivation for nicotine and nicotine seeking.
abstract: The cannabinoid system appears to play a critical facilitative role in mediating the reinforcing effects of nicotine and relapse to nicotine-seeking behaviour in abstinent subjects based on the actions of cannabinoid (CB) receptor antagonists. However, the effects of CB receptor stimulation on nicotine self-administration and reinstatement have not been systematically studied. Here, we studied the effects of WIN 55,212-2, a CB1/2 agonist, on intravenous nicotine self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement in rats. The effects of WIN 55,212-2 on responding for food under similar schedules were also studied. In addition, the effects of WIN 55,212-2 on nicotine- and cue-induced reinstatement of nicotine seeking were also studied, as well as the effects of WIN 55,212-2 on nicotine discrimination. WIN 55,212-2 decreased nicotine self-administration under the FR schedule. However, co-administration of WIN 55,212-2 with nicotine decreased responding for food, which suggests that this effect was non-selective. In contrast, WIN 55,212-2 increased both nicotine self-administration and responding for food under the PR schedule, produced dose-dependent reinstatement of nicotine seeking, and enhanced the reinstatement effects of nicotine-associated cues. Some of these effects were reversed by the CB1 antagonist rimonabant, but not by the CB2 antagonist AM630. In the drug discrimination tests between saline and 0.4 mg/kg nicotine, WIN 55,212-2 produced no nicotine-like discriminative effects but significantly potentiated discriminative stimulus effects of nicotine at the low dose through a CB1-receptor-dependent mechanism. These findings indicate that cannabinoid CB1-receptor stimulation increases the reinforcing effects of nicotine and precipitates relapse to nicotine-seeking behaviour in abstinent subjects. Thus, modulating CB1-receptor signalling might have therapeutic value for treating nicotine dependence.
authors.affiliation: Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Canada.
authors.forename: Islam
authors.initials: I
authors.lastname: Gamaleddin
authors.forename: Carrie
authors.initials: C
authors.lastname: Wertheim
authors.forename: Andy Z X
authors.initials: AZ
authors.lastname: Zhu
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Coen
authors.forename: Kiran
authors.initials: K
authors.lastname: Vemuri
authors.forename: Alex
authors.initials: A
authors.lastname: Makryannis
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
authors.forename: Bernard
authors.initials: B
authors.lastname: Le Foll
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D016739:Behavior, Addictive / Q000139:chemically induced; D001522:Behavior, Animal; D048588:Benzoxazines / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004192:Discrimination, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009042:Motivation / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D009538:Nicotine / Q000008:administration & dosage*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology; D000077285:Rimonabant; D012646:Self Administration / Q000706:statistics & numerical data; D014029:Tobacco Use Disorder
chemical_list: D000701:Analgesics, Opioid; D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D009538:Nicotine; D000077285:Rimonabant