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 smoking 1 . Accumulated evidence indicates that nicotine is the component of tobacco smoke that leads to addiction 2 , 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 animals 3 . Nevertheless, nicotine-withdrawal symptoms, including depressed mood, anxiety, irritability and craving 4 , 5 in dependent subjects may contribute to the addictive liability of nicotine 6 , 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 antagonist 8 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 abuse 9 , 10 , 11 , 12 , 13 , and may constitute an important motivational factor that contributes to craving, relapse and continued tobacco consumption in humans 7 .