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.
Braida
Daniela
D
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy.
Capurro
Valeria
V
Zani
Alessia
A
Rubino
Tiziana
T
Viganò
Daniela
D
Parolaro
Daniela
D
Sala
Mariaelvina
M
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