title: Evaluation of WIN 55,212-2 self-administration in rats as a potential cannabinoid abuse liability model.
abstract: Because Δ(9)-tetrahydrocannabinol (THC) has been a false negative in rat intravenous self-administration procedures, the evaluation of the abuse potential of candidate cannabinoid medications has proved difficult. One lab group has successfully trained self-administration of the aminoalkylindole WIN55,212-2 in rats; however, their results have not been independently replicated. The purpose of this study was to extend their model by using a within-subjects design, with the goal of establishing a robust method suitable for substitution testing of other cannabinoids. Male Long-Evans rats were trained to self-administer WIN55,212-2 (0.01 mg/kg/infusion) on a fixed ratio 3 schedule. Dose-effect curves for WIN55,212-2 were determined, followed by vehicle substitution and a dose-effect curve with THC. WIN55,212-2 self-administration was acquired; however, substitution with THC did not maintain responding above vehicle levels. Dose-dependent attenuation by rimonabant confirmed CB1 receptor mediation of WIN55,212-2's reinforcing effects. Vehicle substitution resulted in a session-dependent decrease in responding (i.e., extinction). While this study provides systematic replication of previous studies, lack of substitution with THC is problematic and suggests that WIN55,212-2 self-administration may be of limited usefulness as a screening tool for detection of the reinforcing effects of potential cannabinoid medications. Clarification of underlying factors responsible for failure of THC to maintain self-administration in cannabinoid-trained rats is needed.
authors.affiliation: RTI International, Research Triangle Park, NC27709-2194, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lefever
authors.affiliation: RTI International, Research Triangle Park, NC27709-2194, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Marusich
authors.affiliation: RTI International, Research Triangle Park, NC27709-2194, USA.
authors.forename: Kateland R
authors.initials: KR
authors.lastname: Antonazzo
authors.affiliation: RTI International, Research Triangle Park, NC27709-2194, USA. Electronic address: jwiley@rti.org.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D048588:Benzoxazines / Q000008:administration & dosage*; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage*; D002186:Cannabinoids / Q000008:administration & dosage*; D003216:Conditioning, Operant; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage; D008297:Male; D002189:Marijuana Abuse / Q000175:diagnosis / Q000209:etiology / Q000523:psychology; D023421:Models, Animal; D009025:Morpholines / Q000008:administration & dosage*; D009281:Naphthalenes / Q000008:administration & dosage*; D051381:Rats; D020318:Rats, Long-Evans; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol
keywords: Abuse liability; Cannabinoids; Rats; Self-administration; WIN55,212-2; Δ(9)-Tetrahydrocannabinol