Molecular mechanisms underlying the motivational effects of nicotine

Abstract

In addition to the primary rewarding properties of nicotine and the alleviation of withdrawal symptoms, cues associated with smoking are critical contributors to maintenance of smoking behavior. Nicotine-paired cues are also critical for precipitating relapse after smoking cessation. An accumulation of evidence suggests that repeated exposure to tobacco, including the primary psychoactive ingredient, nicotine, changes brain neurochemistry in a way that promotes the control that cues associated with smoking or other rewards have over behavior. This chapter will consider the neurochemical mechanisms underlying these neuroadaptations. Targeting these molecular alterations may provide novel treatments for smoking cessation.

Figure 1. Nicotine drives associations with environmental cues that, in turn, drive nicotine intake

Exposure to environmental cues paired with nicotine self-administration greatly increases nicotine intake. Conversely, exposure to nicotine increases the ability of cues to drive responding for rewarding stimuli (conditioned reinforcement). It is clear that α4/β2* nAChRs are important for both nicotine reinforcement and for the ability of nicotine to increase conditioned reinforcement. Other nAChR subtypes, including α6/β3* and α7* nAChRs may also contribute to these processes. D3 type dopamine receptors (D3R), μ-opioid receptors (μR), and the transcription factor CREB can contribute to the ability of nicotine-paired cues to drive behavior. Targeting these molecular processes could result in novel treatments for smoking cessation.