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The plant-derived hallucinogen, salvinorin A, produces κ-opioid agonist-like discriminative effects in rhesus monkeys

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Abstract

Rationale

Salvinorin A is the active component of the hallucinogenic plant Salvia divinorum. The potential mode of action of this hallucinogen was unknown until recently. A recent in vitro study detected high affinity and efficacy of salvinorin A at κ-opioid receptors. It was postulated that salvinorin A would produce discriminative stimulus effects similar to those of a high efficacy κ-agonist (U69,593) in rhesus monkeys.

Methods

Monkeys were previously trained to discriminate U69,593 (0.0056 or 0.013 mg/kg; SC) from vehicle in a food-reinforced FR20 (fixed ratio 20) operant conditioning procedure (n=3). The ability of salvinorin A to cause generalization (≥90% U69,593-appropriate responding) was examined in time course and cumulative dose-effect curve studies.

Results

All subjects dose-dependently emitted full U69,593-appropriate responding after salvinorin A (0.001–0.032 mg/kg, SC). Salvinorin A-induced generalization started 5–15 min after injection, and dissipated by 120 min. The opioid antagonist quadazocine (0.32 mg/kg) fully blocked the effects of salvinorin A. The κ-selective antagonist GNTI (1 mg/kg; 24 h pretreatment) did not cause significant antagonism of the effects of salvinorin A (GNTI, under these conditions, was only effective as an antagonist in two of three monkeys). The NMDA antagonist ketamine (0.1–3.2 mg/kg) was not generalized by any subject, indicating that not all compounds that produce hallucinogenic or psychotomimetic effects in humans are generalized by subjects trained to discriminate U69,593.

Conclusions

The naturally occurring hallucinogen salvinorin A produces discriminative stimulus effects similar to those of a high efficacy κ-agonist in non-human primates.

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Acknowledgement

The present studies were supported by National Institutes of Health/NIDA grants DA11113 (E.R.B.), DA05130 and DA00049 (M.J.K.).

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Authors and Affiliations

  1. The Rockefeller University, 1230 York Avenue, Box 171, New York, NY, 10021, USA

    Eduardo R. Butelman, Todd J. Harris & Mary Jeanne Kreek

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  1. Eduardo R. Butelman
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  2. Todd J. Harris
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  3. Mary Jeanne Kreek
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Correspondence to Eduardo R. Butelman.

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Butelman, E.R., Harris, T.J. & Kreek, M.J. The plant-derived hallucinogen, salvinorin A, produces κ-opioid agonist-like discriminative effects in rhesus monkeys. Psychopharmacology 172, 220–224 (2004). https://doi.org/10.1007/s00213-003-1638-0

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  • DOI: https://doi.org/10.1007/s00213-003-1638-0

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