title: The novel cannabinoid CB1 receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats.
abstract: Drugs that interfere with cannabinoid CB1 transmission suppress various food-motivated behaviors, and it has been suggested that such drugs could be useful as appetite suppressants. Biochemical studies indicate that most of these drugs assessed thus far have been CB1 inverse agonists, and although they have been shown to suppress food intake, they also appear to induce nausea and malaise. The present studies were undertaken to characterize the behavioral effects of AM4113, which is a CB1 neutral antagonist, and to examine whether this drug can reduce food-reinforced behaviors and feeding on diets with varying macronutrient compositions. Biochemical data demonstrated that AM4113 binds to CB1 receptors, but does not show inverse agonist properties (ie no effects on cyclic-AMP production). In tests of spontaneous locomotion and analgesia, AM4113 reversed the effects of the CB1 agonist AM411. AM4113 suppressed food-reinforced operant responding with rats responding on fixed ratio (FR) 1 and 5 schedules of reinforcement in a dose-dependent manner, and also suppressed feeding on high-fat, high-carbohydrate, and lab chow diets. However, in the same dose range that suppressed feeding, AM4113 did not induce conditioned gaping, which is a sign of nausea and food-related malaise in rats. These results suggest that AM4113 may decrease appetite by blocking endogenous cannabinoid tone, and that this drug may be less associated with nausea than CB1 inverse agonists.
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Sink
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McLaughlin
authors.forename: Jodi Anne T
authors.initials: JA
authors.lastname: Wood
authors.forename: Cara
authors.initials: C
authors.lastname: Brown
authors.forename: Pusheng
authors.initials: P
authors.lastname: Fan
authors.forename: V Kiran
authors.initials: VK
authors.lastname: Vemuri
authors.forename: Yan
authors.initials: Y
authors.lastname: Peng
authors.forename: Yan
authors.initials: Y
authors.lastname: Pang
authors.forename: Teresa
authors.initials: T
authors.lastname: Olszewska
authors.forename: Teresa
authors.initials: T
authors.lastname: Olzewska
authors.forename: Ganesh A
authors.initials: GA
authors.lastname: Thakur
authors.forename: Alex
authors.initials: A
authors.lastname: Makriyannis
authors.forename: Linda A
authors.initials: LA
authors.lastname: Parker
authors.forename: John D
authors.initials: JD
authors.lastname: Salamone
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D004347:Drug Interactions; D004435:Eating / Q000187:drug effects*; D008297:Male; D009043:Motor Activity; D009325:Nausea / Q000139:chemically induced*; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology
chemical_list: C496392:(-)-adamantyl-delta8-tetrahydrocannabinol; C529765:AM4113; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D013759:Dronabinol; D000242:Cyclic AMP; D000218:Adamantane