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

Background and purpose: Drugs targeting brain κ‐opioid receptors produce profound alterations in mood. In the present study we investigated the possible anxiolytic‐ and antidepressant‐like effects of the κ‐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. κ‐Opioid receptor involvement was investigated pretreating animals with the κ‐opioid receptor antagonist, nor‐binaltorphimine (1 or 10 mg·kg−1), while direct or indirect activity at CB1 cannabinoid receptors was evaluated with the CB1 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 mg·kg−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 µg·kg−1), exhibited both anxiolytic‐ and antidepressant‐like effects that were prevented by nor‐binaltorphimine or AM251 (0.5 or 3 mg·kg−1). Salvinorin A reduced fatty acid amide hydrolase activity in amygdala but had very weak affinity for cannabinoid CB1 receptors. Conclusions and implications: The anxiolytic‐ and antidepressant‐like effects of Salvinorin A are mediated by both κ‐opioid and endocannabinoid systems and may partly explain the subjective symptoms reported by recreational users of S. divinorum.