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Role of 5-HT2C receptors in effects of monoamine releasers on intracranial self-stimulation in rats

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Abstract

Rationale

Many monoamine releasers are abused by humans and produce abuse-related facilitation of intracranial self-stimulation (ICSS) in rats. Facilitation of ICSS in rats can be limited by monoamine releaser-induced serotonin (5-HT) release, but receptors that mediate 5-HT effects of monoamine releasers are unknown.

Objectives

The aim of this study is to investigate whether 5-HT2C receptor activation is necessary for rate-decreasing effects produced in an ICSS procedure in rats by the 5-HT-selective monoamine releaser fenfluramine and the non-selective releasers napthylisopropylamine (PAL-287) and (+)-3,4-methylenedioxymethamphetamine ((+)-MDMA).

Methods

Adult male Sprague-Dawley rats with electrodes implanted in the medial forebrain bundle were trained to lever press for brain stimulation under a “frequency-rate” ICSS procedure. Effectiveness of the 5-HT2C antagonist SB 242,084 was evaluated to block rate-decreasing effects produced by (1) the 5-HT2C agonist Ro 60-0175, (2) the 5-HT-selective releaser fenfluramine, and (3) the mixed-action dopamine (DA)/norepinephrine (NE)/5-HT releasers PAL-287 (1.0–5.6 mg/kg) and (+)-MDMA (1.0–3.2 mg/kg). For comparison, effectiveness of SB 242,084 to alter rate-decreasing effects of the kappa-opioid receptor agonist U69,593 and rate-increasing effects of the DA>5-HT releaser amphetamine was also examined.

Results

SB 242,084 pretreatment blocked rate-decreasing effects of Ro 60-0175 and fenfluramine, but not the rate-decreasing effects of U69,593 or the rate-increasing effects of amphetamine. SB 242,084 blunted the rate-decreasing effects and enhanced expression of rate-increasing effects of PAL-287 and (+)-MDMA.

Conclusions

These data suggest that 5-HT2C receptor activation contributes to rate-decreasing effects that are produced by selective and mixed-action 5-HT releasers in rats and that may oppose and limit the expression of abuse-related ICSS facilitation by these compounds.

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Acknowledgments

These studies were supported by the National Institute of Health grants F30DA034478 (CTB), R01-DA033930 (SSN), and R01-DA012790 (BEB).

Conflict of interest

There are no other conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th St., PO Box 980613, Richmond, VA, 23298, USA

    Clayton T. Bauer, Matthew L. Banks & S. Stevens Negus

  2. Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, USA

    Bruce E. Blough

Authors
  1. Clayton T. Bauer
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  2. Matthew L. Banks
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  3. Bruce E. Blough
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  4. S. Stevens Negus
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Correspondence to S. Stevens Negus.

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Bauer, C.T., Banks, M.L., Blough, B.E. et al. Role of 5-HT2C receptors in effects of monoamine releasers on intracranial self-stimulation in rats. Psychopharmacology 232, 3249–3258 (2015). https://doi.org/10.1007/s00213-015-3982-2

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  • DOI: https://doi.org/10.1007/s00213-015-3982-2

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