Hallucinatory and rewarding effect of salvinorin A in zebrafish: kappa-opioid and CB1-cannabinoid receptor involvement.
BACKGROUND
The hallucinatory effect and potential abuse of salvinorin A, the major ingredient of Salvia divinorum, has not been documented in animals.


OBJECTIVE
The effects of salvinorin A on the zebrafish (Danio rerio) model, through its swimming behavior and conditioned place preference (CPP) task, was studied.


METHODS
Swimming activity was determined in a squared observational chamber after an i.m. treatment of salvinorin A (0.1-10 microg/kg). For the CPP test, zebrafish were given salvinorin A (0.2 and 1 microg/kg) or vehicle and evaluated in a two-compartment chamber.


RESULTS
Salvinorin A (0.1 and 0.2 microg/kg) induced accelerated swimming behavior in comparison with vehicle, whereas a "trance-like" effect, at doses as 5 and 10 microg/kg, was obtained. Pretreatment with the kappa-opioid antagonist, nor-binaltorphimine (nor-BNI; 10 mg/kg) and the cannabinoid type 1 (CB(1)) antagonist, rimonabant (1 mg/kg), blocked salvinorin A-induced both stimulating and depressive effects obtained at a dose of 0.2 and 10 microg/kg, respectively. In the CPP test, salvinorin A (0.2 and 0.5 microg/kg) produced an increase in the time spent in the drug-associated compartment. A dose of 1 microg/kg produced no effect, whereas a dose of 80 microg/kg induced aversion. Pretreatment with nor-BNI or rimonabant fully reversed the reinforcing properties of salvinorin A (0.5 microg/kg).


CONCLUSIONS
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.
Braida
Daniela
D
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Via Vanvitelli 32, 20129, Milan, Italy. daniela.braida@unimi.it
Limonta
Valeria
V
Pegorini
Simona
S
Zani
Alessia
A
Guerini-Rocco
Chiara
C
Gori
Enzo
E
Sala
Mariaelvina
M
D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D045785:Diterpenes, Clerodane; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology*; 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; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000378:metabolism; D012054:Reinforcement, Psychology; D015203:Reproducibility of Results; D012201:Reward; D000077285:Rimonabant; D013550:Swimming; D013997:Time Factors; D015027:Zebrafish / Q000378:metabolism*
D004224:Diterpenes; D045785:Diterpenes, Clerodane; D006213:Hallucinogens; D009292:Narcotic Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D000077285:Rimonabant; C090499:salvinorin A