Pharmacological enhancement of cannabinoid type 1(CBı) receptor

Accumulating evidence suggests that the endocannabinoid^system may play a role in emotional regulation, and thus may be a novel target for antidepressant pharmacotherapeutics. This experiment aimed to assess whether enhanced CBi receptor activity possesses antidepressant properties. To examine the effect of modulation of cannabinoid activity on behaviors in the rat Porsolt forced swim test, we administered 1 and 5 mg/kg doses of the endocannabinoid uptake inhibitor AM404; 1, 2.5 and 5 mg/kg of the sleep-inducing lipid oleamide, which may possess cannabinoidergic properties; 5, 10 and 25 ug/kg doses of HU-210, a potent CBi receptor agonist; and 1 and 5 mg/kg doses of AM 251, a selective CBi receptor antagonist, and scored the expression of immobility, swimming and struggling during a 5 min test session. Administration of AM404 caused a dose dependent decrease in immobility that was blocked by pretreatment with AM 251. Oleamide also elicited a dose dependent decrease in immobility that was similarly prevented by pretreatment with AM251. Administration of the antagonist AM 251 alone had no effect on immobility at either dose. Furthermore, the agonist HU-210, at doses of 5 and 25 ug/kg, elicited a reduction in immobility. These data suggest that enhancement of CBi receptor signaling results in antidepressant effects in the forced swim test, and that future research should determine whether elevation of endogenous cannabinoids would be a suitable target for the pharmacotherapy of affective and stress related disorders.Medicine, Faculty ofGraduat