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Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys: kappa opioid and serotonergic mechanisms

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Abstract

Rationale

Kappa agonists can attenuate reinstatement of cocaine-seeking behavior induced by cocaine priming. The mechanisms underlying this effect have not been characterized fully but may have a serotonergic component as kappa agonists also increase the release of serotonin (5-hydroxytryptamine, 5-HT).

Objectives

This study investigated the role of kappa opioid receptor and 5-HT mechanisms in kappa agonist-induced attenuation of cocaine priming in monkeys.

Methods

Squirrel monkeys were trained to self-administer cocaine (0.18–0.3 mg/kg/injection) under a second-order schedule in which drug seeking was maintained jointly by cocaine injections and a cocaine-paired visual stimulus. In extinction sessions, saline was substituted for cocaine, and the cocaine-paired stimulus was omitted. During test sessions, only saline was available for self-administration, and response-contingent presentations of the cocaine-paired stimulus were restored.

Results

Priming injections of cocaine (0.1–1.0 mg/kg) induced reinstatement of drug seeking. Maximal levels of responding were similar to those maintained by active cocaine self-administration. Pretreatment with the kappa agonists enadoline (0.01 mg/kg) and spiradoline (0.3 mg/kg) or the 5-HT transport inhibitors fluoxetine (5.6 mg/kg) and citalopram (10.0 mg/kg) attenuated the priming effects of cocaine, shifting the cocaine dose–response function rightward and downward. Inhibition of cocaine-induced reinstatement of drug seeking by spiradoline and fluoxetine was reversed by R(+)8-hydroxy-2-(di-n-propylamino)tetralin (0.03 mg/kg), a 5HT1A agonist that inhibits 5-HT release. The effects of spiradoline also were reversed by the kappa antagonist nor-binaltorphimine (10.0 mg/kg).

Conclusions

Results suggest that the capacity of kappa opioid agonists to increase extracellular 5-HT levels may at least partially underlie kappa agonist-induced modulation of cocaine seeking.

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Acknowledgments

We thank Kristen Bano, Annemarie Duggan, and Donna Reed for expert technical assistance. This research was supported by DA11928, DA11054, and RR00168.

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Author notes

  1. Daniela Rüedi-Bettschen

    Present address: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham Rd. #611, Little Rock, AR, 72205, USA

Authors and Affiliations

  1. New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, P.O. Box 9102, Southborough, MA, 01772-9102, USA

    Daniela Rüedi-Bettschen, James K. Rowlett, Roger D. Spealman & Donna M. Platt

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  1. Daniela Rüedi-Bettschen
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  2. James K. Rowlett
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Correspondence to Donna M. Platt.

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Rüedi-Bettschen, D., Rowlett, J.K., Spealman, R.D. et al. Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys: kappa opioid and serotonergic mechanisms. Psychopharmacology 210, 169–177 (2010). https://doi.org/10.1007/s00213-009-1705-2

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  • DOI: https://doi.org/10.1007/s00213-009-1705-2

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