Shifting pharmacology of nicotine use and withdrawal: breaking the cycle of drug abuse.

Abstract

Smoking is the leading preventable cause of death, responsible for over 400,000 premature deaths every year in the United States and weighing heavily on an economy with a nearly $200 billion combined cost of health care and lost productivity (1). Despite the deleterious immediate and long-term effects of smoking, only 3% of smokers successfully quit, although 70% of all smokers express the desire to do so (2). Nicotine is the main addictive psychoactive ingredient present in tobacco smoke (3). Chronic exposure to nicotine initiates neuroadaptation; these alterations, in turn, promote continued tobacco use. When a smoker attempts cessation, this new equilibrium maintained by nicotine exposure is disrupted, leading to the withdrawal state. Withdrawal is a series of affective and somatic symptoms that emerge a few hours after nicotine abstinence, reflecting neurochemical imbalance (4); however, the precise nature of this imbalance has remained elusive. Nicotine, as is the case with many other drugs of abuse, is known to have an impact on the dopamine (DA) system (5). Grieder et al. (6) perform a series of elegant experiments using pharmacology and electrophysiology in parallel with genetic and behavioral approaches to examine how the dopaminergic system may be involved in this process. An important aspect of their work is that it highlights the double dissociation of dopaminergic system involvement between acute exposure to nicotine and the chronic withdrawn state with respect to DA neuron activation in the ventral tegmental area (VTA) and the DA receptors that mediate conditioned place aversion (Fig. 1).