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 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. k-Opioid receptor involvement was investigated pretreating animals with the k-opioid receptor antagonist, nor-binaltorphimine (1 or 10 mg·kg ). 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 k-opioid and endocannabinoid systems and may partly explain the subjective symptoms reported by recreational users of S. divinorum.

Taken together, these results indicate that salvinorin A, as is sometimes reported in humans, exhibits rewarding effects, independently from its motor activity, suggesting the usefulness of the zebrafish model to study addictive behavior. These effects appear mediated by activation of both kappa-opioid and cannabinoid CB(1) receptors.

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Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a focal form of epilepsy characterized by seizures occurring during non-REM sleep. We have developed and characterized the first mouse model for ADNFLE type III carrying the V287L mutation of the beta2 subunit of neuronal nicotinic receptor. Mice expressing mutant receptors show a spontaneous epileptic phenotype by electroencephalography with very frequent interictal spikes and seizures. Expression of the mutant beta2 subunit is driven by a neuronal-specific tetracycline-controlled promoter, which allows planned silencing of transgene expression in a reversible fashion and tracking the involvement of mutant receptor in crucial phases of epileptogenesis. We found that restricted silencing during development is sufficient to prevent the occurrence of epileptic seizures in adulthood. Our data indicate that mutant nicotinic receptors are responsible for abnormal formation of neuronal circuits and/or long-lasting alteration of network assembly in the developing brain, thus leading to epilepsy.

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