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The role of noradrenaline and 5-hydroxytryptamine in yohimbine-induced increases in alcohol-seeking in rats

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Abstract

Rationale and objectives

We previously showed that systemic administration of the prototypical alpha-2 noradrenaline (NA) receptor antagonist yohimbine increases alcohol self-administration and reinstatement. Yohimbine also acts as an agonist of 5-hydroxytryptamine (5-HT) 5-HT1A receptors, which have been shown to be involved in alcohol seeking. Here, we determined the contributions of the alpha-2 and 5-HT1A properties of yohimbine to its effects on alcohol seeking.

Methods

The effects of lesions of the dorsal or ventral NA bundles with 6-OHDA on yohimbine-induced alcohol self-administration were first determined in male Wistar rats trained to self-administer alcohol (12% w/v, 0.19 ml per alcohol delivery), and then on reinstatement induced by yohimbine after extinction of the operant response. It was then determined whether the selective alpha-2 antagonist RS-79948 (0.1, 0.2, 0.4 mg/kg) would mimic the effects of yohimbine on self-administration and reinstatement. The effects of the alpha-2 receptor agonist clonidine, or the 5-HT1A antagonist WAY 100,635 were then determined on yohimbine-induced self-administration and reinstatement.

Results

Lesions of the NA systems did not affect yohimbine-induced alcohol self-administration or reinstatement, and RS-79948 did not mimic the effects of yohimbine. Clonidine did not significantly affect increased alcohol self-administration induced by yohimbine, but did attenuate its effects on reinstatement. Blockade of 5-HT1A receptors reduced both yohimbine-induced self-administration and reinstatement.

Conclusions

These results suggest that alpha-2 antagonist properties of yohimbine may play a role in the reinstatement of alcohol-seeking, but not self-administration. On the other hand, yohimbine's actions on 5-HT1A receptors contribute to its effects on both alcohol self-administration and reinstatement.

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Acknowledgments

This work was supported by a grant from the NIAAA (AA13108) to A.D. Lê. The authors would like to thank Dr. Yavin Shaham for his expert advice on this manuscript.

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Authors and Affiliations

  1. Neuroscience Department, Centre for Addiction and Mental Health, Toronto, Canada

    Anh Dzung Lê, Douglas Funk, Stephen Harding, Walter Juzytsch & Paul J. Fletcher

  2. Department of Pharmacology, University of Toronto, Toronto, Canada

    Anh Dzung Lê

  3. Department of Psychiatry, University of Toronto, Toronto, Canada

    Anh Dzung Lê & Paul J. Fletcher

  4. Department of Psychology, University of Toronto, Toronto, Canada

    Paul J. Fletcher

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  1. Anh Dzung Lê
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  2. Douglas Funk
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Correspondence to Anh Dzung Lê.

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Dzung Lê, A., Funk, D., Harding, S. et al. The role of noradrenaline and 5-hydroxytryptamine in yohimbine-induced increases in alcohol-seeking in rats. Psychopharmacology 204, 477–488 (2009). https://doi.org/10.1007/s00213-009-1481-z

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  • DOI: https://doi.org/10.1007/s00213-009-1481-z

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