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

Background and purpose: Drugs targeting brain K-opioid receptors produce profound alterations in mood. In the present study we investigated the possible anxiolytic- and antidepressant-like effects of the K-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 anxiolytlc-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. K-Opioid receptor involvement was investigated pretreating animals with the K-opioid receptor antagonist, nor-binaltorphimine (1 or 10 mg-kg ^-1), while direct or indirect activity at CB ¹ cannabinoid receptors was evaluated with the CB ₁ cannabinoid receptor antagonist, N-(piperidin-l-yl) -5-(4-iodophenyl)-1-(2,4dichlorophenyl)-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 u.g-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 CB ₁ receptors. Conclusions and implications: The anxiolytic- and antidepressant-like effects of Salvinorin A are mediated by both K-opioid and endocannabinoid systems and may partly explain the subjective symptoms reported by recreational users of S. divinorum.