PT  - JOURNAL ARTICLE
AU  - Paul J. Kenny
AU  - Athina Markou
TI  - Conditioned Nicotine Withdrawal Profoundly Decreases the Activity of Brain Reward Systems
AID  - 10.1523/JNEUROSCI.4785-04.2005
DP  - 2005 Jun 29
TA  - The Journal of Neuroscience
PG  - 6208--6212
VI  - 25
IP  - 26
4099  - http://www.jneurosci.org/content/25/26/6208.short
4100  - http://www.jneurosci.org/content/25/26/6208.full
SO  - J. Neurosci.2005 Jun 29; 25
AB  - 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-β-erythroidine (DHβE; 3 mg/kg) for 4 d consecutively; ICSS thresholds were assessed before and immediately after DHβE 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, DHβE 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.