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Dramatic decreases in brain reward function during nicotine withdrawal


Tobacco smoking is a worldwide public health problem. In the United States alone, over 400,000 deaths and $50 billion in medical costs annually are directly attributed to smoking1. Accumulated evidence indicates that nicotine is the component of tobacco smoke that leads to addiction2, but the means by which nicotine produces addiction remain unclear. Nicotine is less effective as a positive reinforcer than other drugs of abuse in non-dependent animals3. Nevertheless, nicotine-withdrawal symptoms, including depressed mood, anxiety, irritability and craving4,5 in dependent subjects may contribute to the addictive liability of nicotine6,7. We show here that spontaneous nicotine withdrawal in rats resulted in a significant decrease in brain reward function, as measured by elevations in brain reward thresholds, which persisted for four days. Further, systemic injections of a competitive nicotinic-receptor antagonist8 led to a dose-dependent increase in brain reward thresholds in chronic nicotine-treated rats. The decreased function in brain reward systems during nicotine withdrawal is comparable in magnitude and duration to that of other major drugs of abuse9,10,11,12,13, and may constitute an important motivational factor that contributes to craving, relapse and continued tobacco consumption in humans7.

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Figure 1: Intracranial self-stimulation (ICSS) reward thresholds in rats (expressed as a percentage of the mean (±s.e.m.) baseline reward threshold).
Figure 2: Overall somatic withdrawal signs.


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This research was funded by a Novartis grant to A.M., National Institute on Drug Abuse (NIDA, USA) grants to A.M. and G.F.K., and a HIDA Individual National Research Service Award to M.P.E.-J. This is publication number 11286-NP from The Scripps Research Institute. We thank M.Arends for assistance with manuscript preparation.

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Correspondence to Athina Markou.

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Epping-Jordan, M., Watkins, S., Koob, G. et al. Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393, 76–79 (1998).

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