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The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats

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Abstract

Rationale and objectives

Yohimbine is an alpha-2 adrenoreceptor antagonist that provokes stress- and anxiety-like responses in both humans and laboratory animals. In rats, yohimbine increases operant alcohol self-administration and reinstates alcohol seeking. In this study, we assess whether these effects of yohimbine are attenuated by systemic injections of the corticotrotropin-releasing factor 1 (CRF1) receptor antagonist antalarmin.

Materials and methods

In Exp. 1, we trained rats to lever press for alcohol solutions (12% w/v, 1 h/day) over several weeks; during training, the response requirement was increased from a fixed-ratio-1 (FR-1) to a fixed-ratio-3 (FR-3) reinforcement schedule. We then tested the effect of antalarmin (10 or 20 mg/kg) on yohimbine (1.25 mg/kg)-induced increases in operant alcohol self-administration (FR-3 reinforcement schedule). Subsequently, we assessed the effect of antalarmin on yohimbine-induced increases in plasma corticosterone levels in the previously self-administering rats. In Exp. 2, we trained the rats to self-administer alcohol as in Exp. 1, and after extinction of the alcohol-reinforced lever responding over 13 days, we tested antalarmin’s effect on yohimbine-induced reinstatement of alcohol seeking.

Results

Yohimbine increased operant alcohol self-administration and reinstated alcohol seeking after extinction. These effects of yohimbine were attenuated by antalarmin. Antalarmin injections in the absence of yohimbine had no effect on either operant alcohol self-administration or extinction responding. Antalarmin had no effect on yohimbine-induced corticosterone release in alcohol-experienced rats.

Conclusions

These results suggest that extrahypothalamic CRF1 receptors are involved in the effect of yohimbine on operant alcohol self-administration and on relapse to alcohol seeking and support the notion that CRF1 receptor antagonists should be considered in alcohol addiction treatment.

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Acknowledgements

We are grateful to Dr. Herbert Kronzucker and Mark Szczerba, Division of Life Sciences, University of Toronto at Scarborough, for allowing us to use his laboratory’s resources for the corticosterone assay. These experiments were funded by a grant from the National Institutes of Alcohol and Alcohol Abuse (AD Le). P. Marinelli is supported by postdoctoral fellowships from the Centre for Addiction and Mental Health and the Ontario Mental Health Foundation.

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Authors and Affiliations

  1. Department of Neuroscience, Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Peter W. Marinelli, Douglas Funk, Walter Juzytsch, Stephen Harding & A. D. Lê

  2. Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA

    Kenner C. Rice & Yavin Shaham

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

    A. D. Lê

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

    A. D. Lê

  5. Department of Neurosciences, CAMH, 33 Russell St., Toronto, ON, M5S 2S1, Canada

    Peter W. Marinelli

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  1. Peter W. Marinelli
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Correspondence to Peter W. Marinelli.

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Marinelli, P.W., Funk, D., Juzytsch, W. et al. The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology 195, 345–355 (2007). https://doi.org/10.1007/s00213-007-0905-x

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