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Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum

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Abstract

Rationale

Acute systemic administration of salvinorin A, a naturally occurring κ-opioid receptor (KOPr) agonist, decreases locomotion and striatal dopamine (DA) overflow.

Objectives

Conventional and quantitative microdialysis techniques were used to determine whether salvinorin A infusion into the dorsal striatum (DSTR) decreases DA overflow by altering DA uptake or release. The influence of repeated salvinorin A administration on basal DA dynamics and cocaine-evoked alterations in DA overflow and locomotion was also assessed.

Materials and methods

Salvinorin A was administered via the dialysis probe (0; 20–200 nM) or via intraperitoneal (i.p.) injection (1.0 or 3.2 mg/kg per day × 5 days). The effects of a challenge dose of cocaine were examined 48 h after repeated salvinorin treatment.

Results

Retrodialysis of salvinorin A produced a dose-related, KOPr antagonist reversible, decrease in DA levels. Extracellular DA levels were decreased whereas DA extraction fraction, which provides an estimate of DA uptake, was unaltered. In contrast to its acute administration, repeated salvinorin A administration did not modify dialysate DA levels. Similarly, neither basal extracellular DA levels nor DA uptake was altered. Unlike synthetic KOPr agonists, prior repeated administration of salvinorin A did not attenuate the locomotor activating effects of an acute cocaine (20 mg/kg, i.p.) challenge. However, cocaine-evoked DA overflow was enhanced.

Conclusions

These data demonstrate that acute, but not repeated, salvinorin A administration decreases mesostriatal neurotransmission and that activation of DSTR KOPr is sufficient for this effect. Differences in the interaction of salvinorin and synthetic KOPr agonists with cocaine suggest that the pharmacology of these agents may differ.

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Acknowledgements

This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse. The experiments comply with the current laws of the US, and the authors have no financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. We thank Thomas Prisinzano, Ph.D. for his discussions and support of these studies. We also thank Eric Oh for his technical assistance and Jennifer Davis for her help with editing.

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Authors and Affiliations

  1. Integrative Neuroscience Section, NIH/NIDA Intramural Research Program, 333 Cassell Drive, Baltimore, MD, 21224, USA

    Brenda J. Gehrke, Vladimir I. Chefer & Toni S. Shippenberg

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  1. Brenda J. Gehrke
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  2. Vladimir I. Chefer
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  3. Toni S. Shippenberg
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Correspondence to Brenda J. Gehrke.

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Gehrke, B.J., Chefer, V.I. & Shippenberg, T.S. Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum. Psychopharmacology 197, 509–517 (2008). https://doi.org/10.1007/s00213-007-1067-6

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  • DOI: https://doi.org/10.1007/s00213-007-1067-6

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