Cannabinoid type I (CB₁) receptor activation in the forced swim test (FST) and on locomotor activity (LMA) was examined by manipulating the endogenous agonist anandamide (AEA). AEA modifier URB597 prevents AEA metabolism and AM404 inhibits the reuptake of AEA in post synaptic neurons.

Antidepressant-like behavior was measured using time spent immobile (sec) in the FST, and distance traveled (cm), average velocity (cm/sec), entries into the center zone (#), and time spent in the center zone (min) in the open field test. LMA before (Pre-FST1), immediately after (Post-FST1), and a week after the FST (LMA-FST1) were measured.

Time spent immobile decreased with desipramine (DMI; 10 mg/kg), URB597 (1.0 and 3.2 mg/kg), and AM404 (1.0 mg/kg). Although 1.0 mg/kg of URB597 and AM404 reduced time spent immobile, distance traveled was not impaired. Overall, the decreases in time spent immobile were not because of LMA solely, and URB597 and AM404 have antidepressant properties.