glyceryl-2-arachidonate and Anorexia

Stress is known to reduce food intake. Many aspects of the stress response and feeding are regulated by the endocannabinoid system, but the roles of anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in stress-induced anorexia are unclear.. Effects of acute restraint stress on endocannabinoids were investigated in male Sprague-Dawley rats. Systemic and central pharmacological inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) was used to assess the effects of elevated AEA and 2-AG on homeostatic feeding and on food consumption after stress. Animals were pretreated with the FAAH inhibitor, PF-04457845, or the MAGL inhibitor, MJN110, before 2 h acute restraint stress or 2 h homecage period without food.. Restraint stress decreased hypothalamic and circulating AEA, with no effect in the gastrointestinal tract, while 2-AG content in the jejunum (but not duodenum) was reduced. PF-04457845 (30 μg), given i.c.v., attenuated stress-induced anorexia via CB. Our data reveal diverse roles for 2-AG and AEA in homeostatic feeding and changes in energy intake following stress.

Topics: Amidohydrolases; Animals; Anorexia; Arachidonic Acids; Carbamates; Duodenum; Eating; Endocannabinoids; Glycerides; Homeostasis; Jejunum; Male; Monoacylglycerol Lipases; Polyunsaturated Alkamides; Rats, Sprague-Dawley; Stress, Psychological; Succinimides

The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB(1)) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling.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Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation.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.

Topics: Amygdala; Animals; Anorexia; Anti-Obesity Agents; Anxiety; Arachidonic Acids; Body Weight; Cannabinoid Receptor Antagonists; Corticosterone; Diet; Dietary Sucrose; Endocannabinoids; Female; Glycerides; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant