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N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison with the effects of N-acetylcysteine on food responding and food seeking

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Abstract

Rationale

Chronic nicotine administration decreases the functioning of the cystine–glutamate antiporter system xc− which is hypothesized to promote nicotine-taking and nicotine-seeking behaviors. N-acetylcysteine (NAC), a cystine pro-drug, increases the activity of the cystine–glutamate antiporter system xc−. Thus, NAC could potentially reverse nicotine-induced alterations in glutamatergic transmission and decrease nicotine taking and seeking.

Objectives and methods

To test this hypothesis in the present study, the effects of acute NAC treatment (30, 60, and 90 mg/kg, i.p.) on nicotine (fixed- and progressive-ratio schedules) and food (fixed-ratio schedule) self-administration were assessed in rats. In addition, the effects of acute NAC treatment on cue-induced reinstatement of nicotine- and food-seeking behaviors were investigated. Finally, the effects of repeated daily NAC administration (60 mg/kg, i.p., 14 days) on nicotine and food self-administration were assessed.

Results

Acute NAC administration decreased nicotine self-administration but not food responding under a fixed-ratio schedule of reinforcement. In addition, acute NAC administration showed a nonsignificant trend in attenuating nicotine self-administration under a progressive-ratio schedule that was similar to the dose–response function under the fixed-ratio schedule. Furthermore, repeated NAC administration decreased nicotine self-administration from day 6 to 14 compared with vehicle treatment, with no indication of tolerance development. By contrast, repeated NAC administration decreased food responding from day 6 to 8 compared with vehicle treatment and showed rapid development of tolerance. Finally, acute NAC administration attenuated cue-induced reinstatement of nicotine and food seeking.

Conclusions

Altogether, these findings suggest that NAC may be useful in promoting smoking cessation in humans.

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Acknowledgments

This work was supported by the National Institutes of Health grant DA11946 to AM. AR-N was supported by the National Science Foundation Training Grant HRD-0331537 to California State University, and MSD was supported by Tobacco-Related Disease Research Program (TRDRP) of the State of California Individual Postdoctoral Fellowship 19FT-0045. The authors thank Mr. Michael Arends for editorial assistance.

Conflicts of interest

Athina Markou has received contract research support from Bristol-Myers Squibb Co., F. Hoffman-La Roche, Pfizer, and Astra-Zeneca, and honoraria/consulting fees from Abbott GmbH and Company, AstraZeneca, and Pfizer during the past 3 years. Dr. Markou has a patent on the use of metabotropic glutamate compounds for the treatment of nicotine dependence. The remaining authors report no financial conflicts of interests.

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Authors and Affiliations

  1. Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive, M/C 0603, La Jolla, CA, 92093-0603, USA

    Ana M. Ramirez-Niño, Manoranjan S. D’Souza & Athina Markou

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  1. Ana M. Ramirez-Niño
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  2. Manoranjan S. D’Souza
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  3. Athina Markou
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Correspondence to Athina Markou.

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Ana M. Ramirez-Niño and Manoranjan S. D'Souza have contributed equally in the preparation of this manuscript.

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Ramirez-Niño, A.M., D’Souza, M.S. & Markou, A. N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison with the effects of N-acetylcysteine on food responding and food seeking. Psychopharmacology 225, 473–482 (2013). https://doi.org/10.1007/s00213-012-2837-3

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