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Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat

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Abstract

Rationale

Bupropion is an atypical antidepressant and the only non-nicotine-based therapy approved for smoking cessation. Its use has raised much debate as to how a non-nicotine-based agent can aid in smoking cessation.

Objectives

We assessed the effects of bupropion on brain reward function under baseline conditions and subsequent to withdrawal from chronic nicotine administration in rats.

Methods

A discrete-trial intracranial self-stimulation paradigm procedure was used that provides one with current intensity thresholds, a measure of reward in rats under baseline conditions and subsequent to withdrawal from chronic nicotine (3.16 mg/kg per day for 7 days via osmotic minipump). Somatic signs were recorded based on a checklist of nicotine abstinence signs in animals withdrawn from nicotine.

Results

Bupropion (10–60 mg/kg) dose-dependently lowered reward thresholds in non-withdrawing subjects indicating an increase in reward. Interestingly, a sub-effective dose of bupropion (5 mg/kg) blocked completely the threshold lowering effects of acute nicotine (0.25 mg/kg). Animals withdrawn from chronic nicotine exhibited increases in somatic signs of withdrawal and elevated brain reward thresholds, which is indicative of "diminished interest or pleasure" (i.e. anhedonia) in the rewarding stimuli. Bupropion (10–40 mg/kg) reversed both the reward deficit and the somatic signs, with the highest dose (40 mg/kg) inducing a protracted reversal of the threshold elevation.

Conclusions

Bupropion acts on multiple levels to alter brain reward circuits influenced by nicotine, in addition to reducing the expression of somatic signs of withdrawal. First, bupropion, unlike other antidepressants, increases brain reward function under baseline conditions in non-withdrawing subjects. Second, at low doses bupropion blocks the rewarding effects of nicotine. Third, bupropion reverses the negative affective aspects of nicotine withdrawal. Such actions are likely to act in concert to mediate the unique anti-smoking properties of bupropion.

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Acknowledgements

The authors would like to thank Mr. Stefan Imobersteg for technical assistance and Mr. Michael Arends for editorial assistance. This work was supported by Tobacco-Related Disease Program grant from the State of California 10RT-0074, National Institute on Drug Abuse grant DA11946, National Institute of Mental Health grant MH62527 and a Novartis Research Grant to A.M. A.W.B. was supported by Individual Postdoctoral Fellowship from the Tobacco-Related Disease Research Program from the State of California 11FT-0112. This is publication number 14934-NP from The Scripps Research Institute.

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  1. John F. Cryan

    Present address: Nervous System Research, Novartis Institutes for BioMedical Sciences, Novartis Pharma AG, WSJ-386.344, 4002, Basel, Switzerland

  2. Karen L. Skjei

    Present address: School of Medicine, University of California, San Francisco, CA 94143, USA

Authors and Affiliations

  1. Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA

    John F. Cryan, Adrie W. Bruijnzeel, Karen L. Skjei & Athina Markou

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  1. John F. Cryan
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Correspondence to Athina Markou.

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A.W.B. and K.L.S. contributed equally to this manuscript

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Cryan, J.F., Bruijnzeel, A.W., Skjei, K.L. et al. Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat. Psychopharmacology 168, 347–358 (2003). https://doi.org/10.1007/s00213-003-1445-7

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