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The Journal of Neuroscience, June 29, 2005, 25(26):6208-6212; doi:10.1523/JNEUROSCI.4785-04.2005

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BRIEF COMMUNICATION
Conditioned Nicotine Withdrawal Profoundly Decreases the Activity of Brain Reward Systems

Paul J. Kenny and Athina Markou

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037

Withdrawal from nicotine decreases the activity of brain reward systems, measured in rats by elevations of intracranial self-stimulation (ICSS) thresholds. This reward deficit is hypothesized to contribute to the persistence of the tobacco habit in tobacco smokers. Accumulating evidence suggests that aspects of drug withdrawal may become conditioned to previously neutral environmental stimuli via pavlovian conditioning processes. Here we investigated whether hedonically neutral stimuli repeatedly paired with nicotine withdrawal gained "affective valence" such that withdrawal-associated conditioned stimuli alone decreased brain reward function. Nicotine-dependent rats were presented with a light/tone conditioned stimulus and injected with the nicotinic receptor antagonist dihydro--erythroidine (DHE; 3 mg/kg) for 4 d consecutively; ICSS thresholds were assessed before and immediately after DHE injection. On the test day, the rats were presented with the conditioned stimulus and injected with saline; next, ICSS thresholds were assessed. During conditioning sessions, DHE elevated reward thresholds, and the magnitude by which thresholds were elevated increased during successive conditioning sessions. These data suggest that withdrawal-associated conditioned stimuli potentiated the magnitude of nicotine withdrawal as their motivational significance increased. Most importantly, on the test day, the conditioned stimulus alone elevated reward thresholds. Similarly, in a separate experiment, withdrawal-associated cues elevated reward thresholds in morphine-dependent rats. These data provide the first empirical verification that conditioned nicotine withdrawal may occur after exposure to withdrawal-paired cues. Moreover, these data demonstrate that withdrawal-paired conditioned stimuli attain negative affective valence and can decrease the activity of brain reward systems, mimicking the reward deficit observed during withdrawal from nicotine and other addictive drugs.

Key words: nicotine; morphine; conditioned withdrawal; pavlovian (classical) conditioning; addiction; craving; relapse

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Received Nov 23, 2004; revised May 23, 2005; accepted May 24, 2005.

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				R. D. Hurt, J. O. Ebbert, J. T. Hays, and D. D. McFadden Treating Tobacco Dependence in a Medical Setting CA Cancer J Clin, September 1, 2009; 59(5): 314 - 326. [Abstract] [Full Text] [PDF]

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