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Effects of repeated withdrawal episodes, nicotine dose, and duration of nicotine exposure on the severity and duration of nicotine withdrawal in rats

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Abstract

Rationale

The aversive aspects of nicotine withdrawal contribute to high relapse rates to tobacco smoking after cessation attempts.

Objectives

To investigate the influence of nicotine dose, duration of nicotine exposure, and withdrawal history on the severity of nicotine withdrawal in rats, as assessed by brain stimulation reward thresholds and somatic signs of withdrawal.

Methods

Repeated spontaneous and precipitated withdrawals were investigated through four successive removals of osmotic minipumps delivering nicotine/saline, or with daily injections of the nicotinic receptor antagonist dihydro-β-erythroidine during chronic nicotine/saline exposure, respectively. The effects of dose and duration of exposure were investigated using minipumps of varying duration delivering different nicotine doses.

Results

Increased duration of nicotine exposure: a) prolonged the duration but did not alter the magnitude of withdrawal-associated threshold elevations; b) increased somatic signs early during withdrawal. Increased total nicotine exposure (i.e. increased dose and exposure duration) increased the duration of threshold elevations (no effect on magnitude) but had no effect on somatic signs. Neither repeated spontaneous nor repeated precipitated withdrawals altered the magnitude of withdrawal significantly.

Conclusions

Increases in total nicotine dose resulted in increased severity of the affective aspects of withdrawal. Further, continuous drug exposure resulted in longer lasting withdrawal than intermittent administration even when the total nicotine dose was the same. There was no correlation between threshold elevations and somatic signs of withdrawal. In conclusion, the severity of nicotine withdrawal is mitigated by characteristics of the drug exposure regimen such as drug dose, duration of exposure and whether exposure is continuous or intermittent.

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Acknowledgements

This is publication number 14312-NP from The Scripps Research Institute. This work was supported by Tobacco-Related Disease Research Program grant 10RT-0074, National Institute on Drug Abuse grant 1RO1 DA11946, and a Novartis Research grant to A.M. The authors would like to thank Ms. Jessica Chevrette for technical assistance, Drs. John F. Cryan and Paul Kenny for helpful comments on the manuscript, and Mr. Michael Arends for editorial assistance.

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

    Karen L. Skjei & Athina Markou

  2. School of Medicine, University of California, San Francisco, CA 94143, USA

    Karen L. Skjei

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  1. Karen L. Skjei
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Correspondence to Athina Markou.

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Skjei, K.L., Markou, A. Effects of repeated withdrawal episodes, nicotine dose, and duration of nicotine exposure on the severity and duration of nicotine withdrawal in rats. Psychopharmacology 168, 280–292 (2003). https://doi.org/10.1007/s00213-003-1414-1

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