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


METHODS
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.


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
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.
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy.
Daniela
D
Braida
Valeria
V
Capurro
Alessia
A
Zani
Tiziana
T
Rubino
Daniela
D
Viganò
Daniela
D
Parolaro
Mariaelvina
M
Sala
D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003511:Cyclohexanols / Q000378:metabolism; D045785:Diterpenes, Clerodane / Q000008:administration & dosage / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004644:Emotions / Q000187:drug effects; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011759:Pyrrolidines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D027544:Salvia / Q000737:chemistry; D013550:Swimming; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D003511:Cyclohexanols; D045785:Diterpenes, Clerodane; D009271:Naltrexone; D009292:Narcotic Antagonists; D010880:Piperidines; D011720:Pyrazoles; D011759:Pyrrolidines; D043884:Receptor, Cannabinoid, CB1; D017473:Receptors, Opioid, kappa; D000099252:Fatty Acid Amide Hydrolases; C543264:Cnr1 protein, rat; C051844:norbinaltorphimine; C103505:AM 251; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C051272:spiradoline; C090499:salvinorin A