Withdrawal from Chronic Nicotine Exposure Alters Dopamine Signaling Dynamics in the Nucleus Accumbens

Background: Unaided attempts to quit smoking commonly fail during the first 2 weeks of the nicotine withdrawal syndrome. Alterations in dopamine (DA) signaling correlate with withdrawal from chronic nicotine exposure, but those changes have not been well-characterized. Methods: Mice were administered nicotine in their drinking water for 4 or 12 weeks. Then nicotine was withheld for 1 to 10 days while DA signaling was characterized with in vivo microdialysis or fast-scan cyclic voltammetry. Results: Upon withdrawal of nicotine, the basal DA concentration in the nucleus accumbens decreased as measured by microdialysis. The length of time that the low basal DA state lasted depended on the length of the chronic nicotine treatment. Microdialysis indicated that acute re-exposure to nicotine during withdrawal temporarily reversed this hypodopaminergic state. Voltammetry measurements supported the microdialysis results by showing that nicotine withdrawal decreased tonic and phasic DA release. The basal DA concentration and tonic DA signals, however, were disproportionately lower than the phasic DA signals. Therefore, the phasic/tonic DA signaling ratio was increased during the withdrawal period. Conclusions: The relative increase in the sensitivity of DA release to phasic stimulation suggests an increase in the signal-to-noise relationship of DA signaling during the withdrawal period. Therefore, the DA signal produced by acute nicotine re-exposure produces a DA response that might reinforce relapse to drug use (i.e., smoking). Because the basal DA concentration is low during withdrawal, therapies aimed at elevating the background DA signal represent a reasonable treatment strategy for nicotine-dependent individuals attempting to quit.