Potential anxiolytic- and antidepressant-like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents.

BACKGROUND AND PURPOSE Drugs targeting brain kappa-opioid receptors produce profound alterations in mood. In the present study we investigated the possible anxiolytic- and antidepressant-like effects of the kappa-opioid receptor agonist salvinorin A, the main active ingredient of Salvia divinorum, in rats and mice. EXPERIMENTAL APPROACH Experiments were performed on male Sprague-Dawley rats or male Albino Swiss mice. The anxiolytic-like effects were tested by using the elevated plus maze, in rats. The antidepressant-like effect was estimated through the forced swim (rats) and the tail suspension (mice) test. kappa-Opioid receptor involvement was investigated pretreating animals with the kappa-opioid receptor antagonist, nor-binaltorphimine (1 or 10 mgxkg(-1)), while direct or indirect activity at CB(1) cannabinoid receptors was evaluated with the CB(1) cannabinoid receptor antagonist, N-(piperidin-1-yl) -5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251, 0.5 or 3 mgxkg(-1)), binding to striatal membranes of naïve rats and assay of fatty acid amide hydrolase in prefrontal cortex, hippocampus and amygdala. KEY RESULTS Salvinorin A, given s.c. (0.001-1000 microgxkg(-1)), exhibited both anxiolytic- and antidepressant-like effects that were prevented by nor-binaltorphimine or AM251 (0.5 or 3 mgxkg(-1)). Salvinorin A reduced fatty acid amide hydrolase activity in amygdala but had very weak affinity for cannabinoid CB(1) receptors. CONCLUSIONS AND IMPLICATIONS The anxiolytic- and antidepressant-like effects of Salvinorin A are mediated by both kappa-opioid and endocannabinoid systems and may partly explain the subjective symptoms reported by recreational users of S. divinorum.