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The discriminative effects of the κ-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects

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Abstract

Rationale

The widely available hallucinogen salvinorin A is a unique example of a plant-derived compound selective for κ-opioid receptors and may produce effects distinct from those of other compounds with classic hallucinogenic or dissociative properties which are also abused in humans.

Objectives

The objective of this study is to characterize the salvinorin A discriminative cue in nonhuman primates with high κ-receptor genetic homology to humans.

Methods

Adult rhesus monkeys (n = 3) were trained to discriminate salvinorin A (0.015 mg/kg, s.c.) from vehicle, in a food-reinforced operant discrimination assay. Parallel studies, using unconditioned behavioral endpoints (facial relaxation and ptosis) also evaluated the κ-opioid receptor mediation of salvinorin A in vivo function.

Results

Monkeys trained to discriminate salvinorin A generalized structurally diverse, centrally penetrating κ-agonists (bremazocine, U69,593, and U50,488). By contrast, μ- and δ-opioid agonists (fentanyl and SNC80, respectively) were not generalized, nor were the serotonergic 5HT2 hallucinogen psilocybin or the dissociative N-methyl-D-aspartic acid antagonist, ketamine. The discriminative effects of salvinorin A were blocked by the opioid antagonist quadazocine (0.32 mg/kg), but not by the 5HT2 antagonist ketanserin (0.1 mg/kg). Consistent with these findings, salvinorin and κ-agonists (e.g., U69,593) produce effects in the unconditioned endpoints (e.g., ptosis), whereas psilocybin was inactive.

Conclusions

These findings support the conclusion that the interoceptive/discriminative cue produced by salvinorin A is mediated by agonism at κ-receptors and is mechanistically distinct from that produced by a classic serotonergic hallucinogen.

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Abbreviations

PT:

Pretreatment

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Acknowledgements

These studies were funded by NIH-NIDA grants DA017369 (ERB), DA018151 (TEP), and DA05130 (MJK).

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Authors and Affiliations

  1. Laboratory on the Biology of Addictive Diseases, The Rockefeller University, Box 171, New York, NY, 10065, USA

    Eduardo R. Butelman, Szymon Rus & Mary Jeanne Kreek

  2. Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS, USA

    Thomas E. Prisinzano

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  1. Eduardo R. Butelman
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  2. Szymon Rus
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  3. Thomas E. Prisinzano
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  4. Mary Jeanne Kreek
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Correspondence to Eduardo R. Butelman.

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Butelman, E.R., Rus, S., Prisinzano, T.E. et al. The discriminative effects of the κ-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects. Psychopharmacology 210, 253–262 (2010). https://doi.org/10.1007/s00213-009-1771-5

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  • DOI: https://doi.org/10.1007/s00213-009-1771-5

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