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GABAB receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice

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Abstract

Rationale

A growing number of studies suggest that γ-aminobutyric acid type-B (GABAB) receptor agonists reduce alcohol use and craving.

Objectives

This study was designed to further clarify behavioral mechanism(s) by which GABAB agonists may decrease alcohol reinforcement.

Methods

Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABAB agonist baclofen (0–17 mg/kg, IP) or SKF 97541 (0–1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABAB agonists was examined in ethanol naive and self-administering mice.

Results

Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABAB agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABAB agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABAB agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol.

Conclusions

GABAB agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABAB agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABAB positive modulation. These data question the safety of prescribing GABAB agonists to alcoholics since these drugs may potentiate ethanol’s sedative/hypnotic effects during relapse.

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Acknowledgements

This work was supported by grants AA09981 and AA011605 to C.W.H. from the National Institute on Alcohol Abuse and Alcoholism and by the Bowles Center for Alcohol Studies.

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Authors and Affiliations

  1. Bowles Center for Alcohol Studies, Department of Psychiatry, Thurston-Bowles Building, University of North Carolina at Chapel Hill, CB#7178, Chapel Hill, NC 27599, USA

    Joyce Besheer, Veronique Lepoutre & Clyde W. Hodge

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  1. Joyce Besheer
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  2. Veronique Lepoutre
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  3. Clyde W. Hodge
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Correspondence to Joyce Besheer.

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Besheer, J., Lepoutre, V. & Hodge, C.W. GABAB receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice. Psychopharmacology 174, 358–366 (2004). https://doi.org/10.1007/s00213-003-1769-3

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  • DOI: https://doi.org/10.1007/s00213-003-1769-3

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