Tobacco use is a global problem with serious
health consequences. Though some
treatment options exist, there remains a great need for new effective pharmacotherapies to aid smokers in maintaining long-term
abstinence. In the present article,
we first discuss the neural mechanisms underlying nicotine reward, and then
review various mechanism-based pharmacological agents for the treatment of
nicotine dependence. An
oversimplified hypothesis of addiction to tobacco is that nicotine is the major
addictive component of tobacco. Nicotine binds to α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) located on dopaminergic, glutamatergic and GABAergic neurons in the mesolimbic dopamine (DA) system, which
causes an increase in extracellular DA in the nucleus accumbens (NAc). That increase in DA reinforces tobacco use, particularly during the
acquisition phase. Enhanced
glutamate transmission to DA neurons in the ventral tegmental area appears to play an important role in this process. In addition, chronic nicotine treatment
increases endocannabinoid levels in the mesolimbic DA system, which indirectly modulates NAc DA release and nicotine reward. Accordingly, pharmacological agents that
target brain acetylcholine, DA, glutamate, GABA, or endocannabonoid signaling systems have been proposed to interrupt nicotine action. Furthermore, pharmacokinetic strategies
that alter plasma nicotine availability, metabolism and clearance also
significantly alter nicotine’s action in the brain. Progress using these pharmacodynamic and pharmacokinetic agents is reviewed. For drugs in each category, we discuss the mechanistic rationale for
their potential anti-nicotine efficacy, major findings in preclinical and
clinical studies, and future research directions.
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