Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors.
Psychopharmacology – May 01, 2005
Source: PubMed
Summary
Intriguingly, a plant-derived hallucinogen called Salvinorin A significantly decreases dopamine levels in a key brain region. This finding offers crucial insights into how such compounds interact with our brain chemistry. Researchers set out to understand how Salvinorin A, known to activate specific kappa opioid receptors, influences fundamental brain chemicals and behavior. Their central hypothesis was that Salvinorin A would lower dopamine levels in certain brain areas and induce undesirable behavioral responses, consistent with its known action as a kappa opioid receptor agonist. To investigate this, two main experiments were conducted using mice. First, scientists employed a technique called in vivo microdialysis to precisely measure changes in dopamine levels within the caudate putamen and nucleus accumbens after administering Salvinorin A. Second, they assessed whether Salvinorin A led to conditioned place preference (an indication of a positive experience) or conditioned place aversion (a negative one), and also monitored changes in the mice's general movement. The results were clear and consistent. Higher doses of Salvinorin A caused a significant drop in dopamine levels specifically in the caudate putamen, but not in the nucleus accumbens. Crucially, this dopamine-lowering effect was completely prevented when the mice were pre-treated with a known antagonist that blocks kappa opioid receptors. Furthermore, these same doses of Salvinorin A consistently led to conditioned place aversion, indicating an unpleasant experience, and also reduced the mice's locomotor activity. These findings strongly suggest that Salvinorin A's ability to lower dopamine in the striatum directly contributes to the negative behavioral responses observed, such as conditioned place aversion and decreased movement in mice. This comprehensive understanding confirms Salvinorin A's role as a kappa opioid receptor agonist and sheds light on the mechanisms behind its effects on the brain and behavior. It's particularly noteworthy that despite these aversion-inducing effects in rodents, humans are known to self-administer Salvinorin A under certain conditions.
Abstract
Salvinorin A is a naturally occurring hallucinogen derived from the plant Salvia divinorum. Salvinorin A is also a potent and selective kappa opioid receptor agonist in vitro. It has been shown that kappa agonists decrease dopamine levels in the caudate putamen and nucleus accumbens and cause conditioned place aversion in rodents. To study the effects of salvinorin A on basal dopamine levels in the caudate putamen and nucleus accumbens, and to determine whether salvinorin A induces conditioned place preference or aversion and changes in locomotor activity in the mouse. In the first experiment, changes in dopamine levels in these brain regions after administration of salvinorin A were measured with in vivo microdialysis. In the second experiment, we examined whether salvinorin A led to conditioned place preference or aversion, and changes in locomotor activity during conditioning sessions. The higher doses of salvinorin A studied (1.0 mg/kg and 3.2 mg/kg, i.p.) significantly decreased dopamine levels in the caudate putamen, but not in the nucleus accumbens, and this effect was completely blocked by pre-injection with 10 mg/kg of the kappa opioid receptor antagonist nor-binaltorphimine. The same doses of salvinorin A caused conditioned place aversion and decreased locomotor activity. The inhibitory effect of salvinorin A on striatal dopamine levels may contribute to its induction of conditioned place aversion and decreases in locomotion in mice. These findings are consistent with the in vitro characterization of salvinorin A as a kappa opioid receptor agonist. It is of interest that a compound such as salvinorin A, that lowers striatal dopamine levels and leads to conditioned place aversion in rodents, is self-administered by humans under certain conditions.