Nicotine produces chronic behavioral sensitization with changes in accumbal neurotransmission and increased sensitivity to re-exposure

Tobacco use is often associated with long-term addiction as well as high risk of relapse following cessation. This is suggestive of persistent neural adaptations, but little is known about the long-lasting effects of nicotine on neural circuits. In order to investigate the long-term effects of nicotine exposure, Wistar rats were treated for 3 weeks with nicotine (0.36mg/kg), and the duration of behavioral and neurophysiological adaptations was evaluated 7 months later. We found that increased drug-induced locomotion persisted 7 months after the initial behavioral sensitization. In vitro analysis of synaptic activity in the core and shell of the nucleus accumbens (nAc) revealed a decrease in input/output function in both regions of nicotine-treated rats as compared to vehicle-treated control rats. In addition, administration of the dopamine D2 receptor agonist quinpirole (5M) significantly increased evoked population spike amplitude in the nAc shell of nicotine-treated rats as compared to vehicle-treated control rats. To test whether nicotine exposure creates long-lasting malleable circuits, animals were re-exposed to nicotine 7 months after the initial exposure. This treatment revealed an increased sensitivity to nicotine among animals previously exposed to nicotine, with higher nicotine-induced locomotion responses than observed initially. In vitro electrophysiological recordings in re-exposed rats detected an increased sensitivity to dopamine D2 receptor activation. These results suggest that nicotine produces persistent neural adaptations that make the system sensitive and receptive to future nicotine re-exposure.