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Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys by direct and indirect activation of 5-HT2C receptors

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Abstract

Rationale

5-Hydroxytryptamine (5-HT) transport inhibitors can attenuate the abuse-related effects of cocaine, and the mechanisms underlying this attenuation may involve activation of 5-HT2C receptors.

Objectives

The objective of this study was to investigate the consequences of direct and indirect pharmacological activation of 5-HT2C receptors on reinstatement of cocaine-seeking behavior induced by cocaine priming and a cocaine-paired stimulus.

Methods

Monkeys were trained to self-administer cocaine under a second-order schedule in which responding was maintained by i.v. cocaine injections and a cocaine-paired stimulus. Drug seeking was extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. During reinstatement tests, the animals received a priming injection of cocaine along with restoration of the cocaine-paired stimulus, but only vehicle was available for self administration.

Results

Pretreatment with either the 5-HT transport inhibitor fluoxetine (5.6 mg/kg) or the 5-HT2C receptor agonist Ro 60–0175 (1 mg/kg) attenuated reinstatement of drug seeking by cocaine priming. The reinstatement-attenuating effects of both drugs were reversed by the 5-HT2C receptor antagonist SB 242084 (0.03–0.56 mg/kg). Ro 60–0175 (1 mg/kg) attenuated cocaine-induced reinstatement of drug seeking regardless of whether priming injections were or were not accompanied by restoration of the cocaine-paired stimulus. Ro 60–0175 (0.56 mg/kg) was equally effective whether it was administered acutely or chronically. Finally, Ro 60–0175 (0.3–1 mg/kg) had observable behavioral effects suggestive of anxiolytic-like properties.

Conclusions

5-HT2C receptor mechanisms play a key role in the modulation of cocaine-induced reinstatement by fluoxetine and Ro 60–0175. Direct activation of 5-HT2C receptors may offer a novel, tolerance-free therapeutic strategy for the prevention of cocaine relapse.

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Acknowledgments

We thank K. Bano, L. Teixeira, and R. Smith for technical assistance.

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Author notes

  1. Daniela Rüedi-Bettschen & Donna M. Platt

    Present address: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, 39216, USA

Authors and Affiliations

  1. Harvard Medical School, New England Primate Research Center, Southborough, MA, USA

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

Authors
  1. Daniela Rüedi-Bettschen
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  2. Roger D. Spealman
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  3. Donna M. Platt
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Corresponding author

Correspondence to Donna M. Platt.

Additional information

This research was supported by DA11054, RR00168, and OD11103.

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Rüedi-Bettschen, D., Spealman, R.D. & Platt, D.M. Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys by direct and indirect activation of 5-HT2C receptors. Psychopharmacology 232, 2959–2968 (2015). https://doi.org/10.1007/s00213-015-3932-z

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  • DOI: https://doi.org/10.1007/s00213-015-3932-z

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