Endocannabinoid regulation of homeostatic feeding and stress-induced alterations in food intake in male rats.

BACKGROUND AND PURPOSE: 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.

EXPERIMENTAL APPROACH: 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.

KEY RESULTS: 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 CB1 receptors, but reduced homeostatic feeding in unstressed animals through an unknown mechanism. On the other hand, systemic administration of MJN110 (10 mg·kg-1 ) reduced feeding, regardless of stress or feeding status and inhibited basal intestinal transit in unstressed rats. The ability of MAGL inhibition to reduce feeding in combination with stress was independent of CB1 receptor signalling in the gut as the peripherally restricted CB1 receptor antagonist, AM6545 did not block this effect.

CONCLUSIONS AND IMPLICATIONS: Our data reveal diverse roles for 2-AG and AEA in homeostatic feeding and changes in energy intake following stress.