Salvinorin A impairs memory function in rats : role of endocannabinoid system

Salvia divinorum is a recreational drug known to induce hallucinatory effects (1). Its main active ingredient, salvinorin A, has been recently found to have reinforcing effects in rats (2). Since hallucinogens are known to interfere with cognitive processes (3), the aim of the present work was to investigate the effect of salvinorin A on different forms of memory (episodic, aversive and spatial) using the object recognition, passive avoidance and 8-arm radial maze tasks, in Wistar rats. Salvinorin A (320-640 μg/kg, s.c.) induced a significant impairment of both episodic and aversive memory. In the object recognition task the drug decreased the time spent exploring a new object in comparison with a familiar one to which rats were exposed 30 min before. In the passive avoidance test salvinorin A decreased the mean latency to re-enter the shock box 24 hours after the animals had received an electric-shock. In the radial maze task no detrimental effect was observed on working memory parameters (total number of errors, number of correct choices and time taken to complete the maze). In contrast, the strategies adopted by rats evaluated through the pattern of arm entry were affected by salvinorin A at all the tested doses (80-640 μg/kg, s.c.), suggesting its ability to induce altered perception of spatial relationship and disorientation. Pre-treatment with AM251 (3 mg/kg i.p.) was successful in contrasting the amnesic effect of salvinorin A (640 μg/kg, s.c.), suggesting an interaction of the compound with the endocannabinoid system. In order to elucidate the neuroanatomical substrates underlying the effect of salvinorin A cFos expression in memory-related brain regions (prefrontal cortex, amygdala, and hippocampus) was investigated. Preliminary results indicate that salvinorin A lowers the amount of cFos expression in the hippocampus and, though to a lesser extent, in the prefrontal cortex and amygdala. Furthermore, salvinorin A appears to increase fatty acid amide hydrolase (FAAH) activity in the prefrontal cortex confirming the involvement of endocannabinoid system. In conclusion, our results demonstrate for the first time that salvinorin A impairs memory function through the endocannabinoid system, probably as a result of the hallucinogenic properties of this recreational drug.