kappa-agonist effects of the hallucinogen Salvinorin A

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DESCRIPTION (provided by applicant): Salvinorin A is the main active component of the hallucinogenic plant, Salvia divinorum. Salvinorin A-containing products have recently become widely available (e.g., on the internet), and there are emerging reports of Salvia divinorum use as a hallucinogen, in the U.S. Very recent in vitro studies identified salvinorin A as a selective, "ultra-high" efficacy kappa-opioid receptor agonist. Salvinorin A (a non-nitrogenous diterpene) is a structurally completely novel ligand for opioid receptors. To date, there is very limited published evidence on the potential in vivo kappa-opioid effects of salvinorin A, in any species. The effects of classic serotonergic hallucinogens abused by humans are thought to be primarily mediated by agonist actions at 5HT2A receptors; salvinorin A does not have affinity at 5HT2A receptors. It is unknown whether the hallucinogenic / behavioral effects of salvinorin A and those of classic serotonergic hallucinogens share common downstream substrates. The Central Hypothesis of this proposal is that salvinorin A has the unique in vivo pharmacological profile of a centrally-penetrating, "ultra-high" efficacy kappa-agonist in nonhuman primates. Salvinorin A's effects will be sensitive to pretreatment by a serotonergic 5HT2A antagonist, indicating common downstream effects of salvinorin A and classic serotonergic hallucinogens. Approach: This proposal focuses on a parametric comparison of the discriminative, neuroendocrine and behavioral effects of salvinorin A to those of the synthetic kappa-agonist, U69,593, and to selected serotonergic hallucinogens. Specifically, the proposed studies would determine the potency, effectiveness (apparent efficacy), receptor selectivity and duration of action of this mechanistically novel hallucinogen in a new salvinorin A drug discrimination, in a neuroendocrine biomarker assay (prolactin release) and in "blind" observational studies, using rating scales for sedation (a prominent effect of kappa-agonists) and other behavioral effects. Antagonism of salvinorin A-induced effects will be systematically characterized with opioid receptor antagonists (e.g., nalmefene and GNTI), and with a selective 5HT2A antagonist. Significance: The proposed studies would determine whether the in vivo effects of salvinorin A are due to "ultra-high" efficacy agonist effects at kappa-opioid receptors, and whether there are interacting pharmacological substrates in the effects of salvinorin A and classic serotonergic hallucinogens, in primates.