Anandamide (AEA) modifiers indirectly modulate CB1 receptor activity in the forced swim test

Evidence indicates that the endocannabinoid system is involved in modulating behavior; however, there is less known about the involvement of the CB1 receptor in behavioral responses to stress and locomotor activity (LMA) together. Therefore, the current study examined the effects of the CB1 receptor activation in the forced swim test (FST) and the open field test. The level of endogenous cannabinoid anandamide (AEA) was pharmacologically manipulated with either URB597 (0.03–3.2 mg/kg) or AM404 (0.32–3.2 mg/kg). URB597 increases AEA by inhibiting fatty acid amide hydrolase (FAAH) metabolism and AM404 increases AEA by inhibiting the reuptake of AEA into post synaptic neuronal cells. The results of the study indicate that select doses of URB597 (1.0 and 3.2 mg/kg) and AM404 (1.0 mg/kg) decreased time spent immobile in the FST, similar to effects observed with the antidepressant desipramine (DMI). Doses of URB597 that decreased time spent immobile also increased LMA, whereas the dose of AM404 that decreased time spent immobile did not alter LMA. These studies demonstrate that AEA modifiers, URB597 and AM404, as well as the antidepressant DMI, are effective at decreasing immobility in response to acute FST exposure. Moreover, the decrease in immobility in the presence of URB597 and AM404 is not explained by changes in LMA as measured by distance traveled. Support: NIH grants R01‐DA002749 and T32‐DA007244.