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The effects of the 5-HT2C receptor antagonist SB242084 on locomotor activity induced by selective, or mixed, indirect serotonergic and dopaminergic agonists

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Abstract

Rationale

The 5-HT2C receptor modulates mesolimbic dopamine (DA) function and the expression of DA-dependent behaviors, including stimulant-induced hyperactivity. The 5-HT2C receptor may also be involved in drug-induced locomotion that is 5-HT-dependent.

Objectives

This study investigated the effects of the 5-HT2C receptor antagonist 6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline (SB242084) on hyperlocomotion induced by psychomotor stimulants with selective, or mixed, actions on serotonergic and/or dopaminergic systems.

Materials and methods

Male Sprague–Dawley rats were treated in the presence or absence of SB242084 with releasers/reuptake inhibitors of DA (amphetamine and methylphenidate), 5-HT (fenfluramine and citalopram), or both 5-HT and DA (MDMA and cocaine). In addition, the effects of SB242084 combined with nicotine, morphine, or the 5-HT1A/1B receptor agonist RU24969 were examined. Locomotor activity was recorded for 2 h.

Results

SB242084 potentiated hyperactivity induced by MDMA (2.5–5 mg/kg), amphetamine (0.5 mg/kg), fenfluramine (5 mg/kg), cocaine (10 mg/kg), and methylphenidate (5 mg/kg). SB242084 modestly potentiated nicotine-induced (0.2–0.4 mg/kg) and morphine-induced (2.5 mg/kg) hyperactivity. SB242084 failed to influence hyperactivity induced by RU24969 (0.5–1 mg/kg) or citalopram (10–20mg/kg).

Conclusion

SB242084 potentiated the locomotor stimulant effects of both indirect DA and 5-HT agonists. This potentiation may reflect two distinct mechanisms. The first involves direct enhancement of DA activity as shown by potentiation of the effects of amphetamine and methylphenidate. The second mechanism reflects an unmasking of stimulatory 5-HT receptors activated by 5-HT releasers (possibly 5-HT1B/2A) through blockade of inhibitory 5-HT2C receptors. The failure of SB242084 to potentiate the effect of citalopram might reflect differences between changes in synaptic levels of 5-HT produced by release compared to reuptake inhibition.

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Acknowledgement

This work was supported by an operating grant from the Canadian Institutes of Health Research to PJF.

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Authors and Affiliations

  1. Section of Biopsychology, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada

    Paul J. Fletcher & Judy Sinyard

  2. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Paul J. Fletcher

  3. Department of Psychology, University of Toronto, Toronto, ON, Canada

    Paul J. Fletcher

  4. NPS Pharmaceuticals, 101 College Street, South Tower, 8th floor, Toronto, ON, M5G 1L8, Canada

    Guy A. Higgins

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Correspondence to Paul J. Fletcher.

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Fletcher, P.J., Sinyard, J. & Higgins, G.A. The effects of the 5-HT2C receptor antagonist SB242084 on locomotor activity induced by selective, or mixed, indirect serotonergic and dopaminergic agonists. Psychopharmacology 187, 515–525 (2006). https://doi.org/10.1007/s00213-006-0453-9

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