Elsevier

Biological Psychiatry

Volume 63, Issue 3, 1 February 2008, Pages 286-292
Biological Psychiatry

Original Article
Involvement of κ-Opioid and Endocannabinoid System on Salvinorin A-Induced Reward

https://doi.org/10.1016/j.biopsych.2007.07.020Get rights and content

Background

The recreational drug, Salvinorin A, derived from the plant of Salvia divinorum, is a potent and selective κ-opioid receptor agonist. The abuse of selective k-agonists is a novel phenomenon, the mechanism of which is not fully understood.

Methods

We investigated salvinorin A given SC on the conditioned place preference (.05–160 μg/kg) and intracerebroventricular (ICV) self-administration (.01–1 μg/infusion) paradigms, in Wistar rats.

Results

The present results demonstrate the rewarding effects of Salvinorin A in a range of doses between .1 and 40 μg/kg SC for conditioned place preference test and .1–.5 μg/infusion for ICV self-administration. Highest doses (160 μg/kg for conditioned place preference test and 1 μg/infusion for ICV self-administration) were aversive. The rewarding effect was antagonized by intraperitoneal (IP) pretreatment with the cannabinoid CB1 receptor antagonist, rimonabant [N-piperidino-5-(4-chlorophenyl)1-(2,4-dichloro phenyl)-4 methyl pyrazole 3-carboxamide] (1 mg/kg), and the κ-opioid receptor antagonist, nor-binaltorphimine (nor-BNI) (10 mg/kg). In the shell of nucleus accumbens, dopamine extracellular levels were increased after administration of salvinorin A (40 μg/kg SC), reaching a maximum value of about 150%.

Conclusions

These data provide the demonstration of the rewarding effects of Salvinorin A through an interaction between κ-opioid and (endo)cannabinoid system in rats.

Section snippets

Animals

Male Wistar rats (Charles River; Calco, Como, Italy) weighing 200–300 g were housed in individual cages in a climatically controlled colony room under a 12/12-hour light/dark cycle (lights on at 8:00 am). Food and water were continuously available, and each animal was handled daily through the 1st week. Then they were randomly assigned to different experimental groups of 10 each. All experiments were performed between 8:00 am and 4:00 pm. Experimental protocols were approved by the local

Spontaneous Motor Activity

Salvinorin A did not affect the mean number of horizontal and vertical counts at any of the doses tested, when compared with vehicle (Figure 2).

Conditioned Place Preference

The development of a conditioned place preference induced by salvinorin A at different doses is shown in Figure 3. The ANOVA revealed significant treatment effect between subjects when comparing the time during the pre- and post-conditioning period in the drug-paired compartment [F(6,49) = 3.48; p < .005]. Thus, post hoc analysis showed that salvinorin

Discussion

Our results demonstrate for the first time the abuse potential of the naturally occurring hallucinogen salvinorin A. Indeed when given at very low dose it is able to induce place preference in rats. These findings likely agree with the rewarding effects recently obtained with salvinorin A in the zebrafish model (26). In accordance with Zhang et al. (16), we also reported a conditioned place aversion at higher doses (1 and 3.2 mg/kg). Differences in the species used and in the route of

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