Protracted cannabinoid administration elicits antidepressant behavioral responses in rats: role of gender and noradrenergic transmission

Research has shown that enhancement of cannabinoid CB(1) receptor activity elicits an antidepressant-like response in the forced swim test (FST); however, the effects of chronic administration of cannabinoid agents in the FST are not well characterized. In Experiment 1, the CB(1) receptor agonist HU-210 (0.1 mg/kg) was administered for 10 days to male rats, following which animals were exposed to the FST. In Experiment 2, the same protocol was utilized; however, prior to the FST animals were co-treated with either prazosin (1 mg/kg; an alpha(1)-adrenoreceptor antagonist) or propranolol (2.5 mg/kg; a beta-adrenoreceptor antagonist). In Experiment 3, the same protocol was employed in both male and female rats, and the role of drug withdrawal was examined by administration of the CB(1) receptor antagonist AM251 (1 mg/kg) prior to the FST. Experiment 1 revealed that HU-210 administration evoked a reduction in immobility and increase in struggling that was identical to that produced by the antidepressant desipramine (10 mg/kg). Experiment 2 revealed that this effect was attenuated by both alpha- and beta-adrenoreceptor antagonists, suggesting noradrenergic involvement in this antidepressant-like profile. Experiment 3 demonstrated that HU-210 administration produced an antidepressant response in both males and females, which was attenuated by the induction of precipitated withdrawal. These results show that protracted administration of a CB(1) receptor agonist produces an antidepressant-like response in the FST in both sexes, which appears to involve the noradrenergic system.