Neuropsychopharmacology. 2013 Jun 24. doi: 10.1038/npp.2013.153. [Epub ahead of print]
Rimonabant precipitates anxiety in rats withdrawn from palatable food: role of the central amygdale.
Blasio A, Iemolo A, Sabino V, Petrosino S, Steardo L, Rice KC, Orlando P, Arturo Iannotti F, Di Marzo V, Zorrilla EP, Cottone P.
Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA.
The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB1) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling.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 (AEA) and 2-arachidonoylglycerol (2-AG) and the CB1 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Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation.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, CB1 receptor mRNA, and protein levels selectively in the CeA. Finally, rimonabant, microinfused directly into the CeA, precipitated anxiety-like behavior and anorexia. Our data shows that (i) the 2-AG-CB1 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-CB1 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. |
