title: Rimonabant precipitates anxiety in rats withdrawn from palatable food: role of the central amygdala.
abstract: The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB(1)) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling. The effects of systemic administration of rimonabant on anxiety-like behavior, food intake, body weight, and adrenocortical activation were assessed in female rats during withdrawal from chronic palatable diet cycling. The levels of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and the CB(1) receptor mRNA and the protein in the central nucleus of the amygdala (CeA) were also investigated. Finally, the effects of microinfusion of rimonabant in the CeA on anxiety-like behavior, and food intake were assessed. Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation. These behavioral observations were accompanied by increased 2-AG, CB(1) receptor mRNA, and protein levels selectively in the CeA. Finally, rimonabant, microinfused directly into the CeA, precipitated anxiety-like behavior and anorexia. Our data show that (i) the 2-AG-CB(1) receptor system within the CeA is recruited during abstinence from palatable diet cycling as a compensatory mechanism to dampen anxiety, and (ii) rimonabant precipitates a negative emotional state by blocking the beneficial heightened 2-AG-CB(1) receptor signaling in this brain area. These findings help elucidate the link between compulsive eating and anxiety, and it will be valuable to develop better pharmacological treatments for eating disorders and obesity.
authors.affiliation: Laboratory of Addictive Disorders, Department of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Blasio
authors.forename: Attilio
authors.initials: A
authors.lastname: Iemolo
authors.forename: Valentina
authors.initials: V
authors.lastname: Sabino
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrosino
authors.forename: Luca
authors.initials: L
authors.lastname: Steardo
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Orlando
authors.forename: Fabio Arturo
authors.initials: FA
authors.lastname: Iannotti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Eric P
authors.initials: EP
authors.lastname: Zorrilla
authors.forename: Pietro
authors.initials: P
authors.lastname: Cottone
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000378:metabolism; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000633:toxicity*; D001007:Anxiety / Q000139:chemically induced* / Q000378:metabolism; D001095:Arachidonic Acids / Q000737:chemistry; D001835:Body Weight / Q000187:drug effects; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D003345:Corticosterone / Q000097:blood; D004032:Diet; D019422:Dietary Sucrose / Q000008:administration & dosage; D063388:Endocannabinoids / Q000737:chemistry; D005260:Female; D005989:Glycerides / Q000737:chemistry; D010880:Piperidines / Q000008:administration & dosage / Q000633:toxicity*; D011720:Pyrazoles / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D000077285:Rimonabant
chemical_list: D019440:Anti-Obesity Agents; D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D019422:Dietary Sucrose; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; D003345:Corticosterone