Conditioned Nicotine Withdrawal Profoundly Decreases the Activity of Brain Reward Systems

Abstract

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. Nicotinedependent rats were presented with a light/tone conditioned stimulus and injected with the nicotinic receptor antagonist dihydro-␤-erythroidine (DH␤E; 3 mg/kg) for 4 d consecutively; ICSS thresholds were assessed before and immediately after DH␤E 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, DH␤E 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 withdrawalpaired 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.

Precipitated Withdrawal From Nicotine Reduces Reinforcing Effects of a Visual Stimulus for Rats

“…The observed decrement in reinforcer effi cacy following mecamylamine -precipitated withdrawal is consistent with previous experiments that showed decrements in conditioning to novelty reward ( Besheer & Bevins, 2003 ) and brain reward pathways ( Epping-Jordan et al, 1998 ;Kenny & Markou, 2005 ;Skjei & Markou, 2003 ) after nicotine withdrawal. These previous fi ndings have been interpreted as affective symptoms of nicotine withdrawal and potential motivators for relapse, namely , through negative reinforcement theory.…”

Neurobiology of Nicotine Addiction: Implications for Smoking Cessation Treatment

“…Thus, cues associated with nicotine withdrawal have the ability to decrease brain reward function. 45 Cigarette smoking is maintained, in part, by such conditioning. People habitually smoke cigarettes in specific situations, such as after a meal, with a cup of coffee or an alcoholic drink, or with friends who smoke.…”

Neurobiology of nicotine dependence

“…ÃÃÃ p!0.001, ÃÃ p!0.01, Ã p!0.05, compared with thresholds obtained on the preconditioning day ( post hoc test after significant one-way analysis of variance); # p!0.05, compared with preconditioning day (paired t-test). Adapted from Kenny & Markou (2005). couple to G q -proteins to activate phospholipase C. In addition, group I receptors couple to intracellular Homer proteins that play an important role in trafficking mGlu receptors in and out of the synapses and functionally connect metabotropic to ionotropic glutamate receptors. Group II (mGlu2 and mGlu3) receptors are primarily found presynaptically and also on glial cells and couple to G i/o proteins to negatively regulate adenylyl cyclase activity.…”