Combined administration of intracerebroventricular CB1 agonist ACEA and systemic TRPV1 agonist capsaicin induces synergistic antidepressant-like effects in rats.

Depression is a distressing mental disorder that affects millions of people worldwide. Current treatments include both psychological and pharmacological approaches. However, delays in clinical improvement and high percentage of patients unresponsive to conventional antidepressants highlight the need to identify novel compounds or strategies with optimal antidepressant actions. We have previously shown the antidepressant-like effects of the intraperitoneal (i.p.) administration of the TRPV1 agonist capsaicin (Cap). Moreover, accumulating evidence indicates that the endocannabinoid system plays a key role in the regulation of mood. To explore the role of cerebral cannabinoid receptor type 1 (CB1) in the antidepressant-like effects of Cap, we assessed the impact of separated and combined administration of Cap (i.p.) and the CB1 agonist ACEA (intracerebroventricularly) on rat's immobility time in the forced swim test. Alike to Cap, we found that ACEA significantly reduced this parameter. Importantly, when combining these compounds, synergistic effects were observed. Contrarily, no impact on the general locomotor activity was detected in the open field test, and no changes in anxiety-related behaviors were noted in the elevated plus maze, for either ACEA alone or its combination with Cap. The present findings suggest that Cap acts through activation of gastrointestinal TRPV1 vagal fibers, while ACEA acts by stimulation of cerebral CB1 receptors. However, more studies are required to elucidate the implied mechanisms of action.