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 (eCB) 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 eCBs 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 determine the potential of elevated AEA and 2-AG to stimulate homeostatic feeding and modulate food consumption after stress. Animals were pretreated with the FAAH inhibitor, PF-04457845, or MAGL inhibitor, MJN110, prior to 2 h acute restraint stress or 2 h homecage period without food.

KEY RESULTS:

Restraint stress resulted in a decrease in hypothalamic and circulating AEA, with no effect in the gastrointestinal tract, while 2-AG content in the jejunum (but not duodenum) was reduced. Intracerebroventricular (icv) administration of PF-04457845 (30 μg), attenuated stress-induced anorexia via CB₁ receptors, yet reduced homeostatic feeding in unstressed animals through an unknown mechanism. On the other hand, systemic administration of MJN110 (10 mg/kg) reduced feeding regardless of stress/feeding condition and inhibited basal intestinal transit in unstressed rats. The ability of MAGL inhibition to reduce feeding in combination with stress was independent of CB₁ signaling in the gut as the peripherally restricted CB₁ antagonist, AM6545 did not block this effect.

CONCLUSION AND IMPLICATIONS:

The current study reveals diverse roles for 2-AG and AEA in homeostatic feeding and changes in energy intake following stress.

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