Mechanism-based medication development for the treatment of nicotine dependence

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Acta Pharmacol Sin 2009 Jun; 30 (6): 723739

Review

Mechanism-based medication development for the treatment of nicotine dependence

Zheng-xiong XI*, Krista SPILLER, Eliot L GARDNER

Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA

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 rst discuss the neural mechanisms underlying nicotine reward, and then review various mechanism-based pharmacological agents for the treatment of nicotine dependence. An oversimplied hypothesis of addiction to tobacco is that nicotine is the major addictive component of tobacco. Nicotine binds to 42 and 7 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 signicantly alter nicotines 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 efcacy, major ndings in preclinical and clinical studies, and future research directions.

Keywords: nicotine; reward; addiction; smoking cessationActa Pharmacologica Sinica (2009) 30: 723739; doi: 10.1038/aps.2009.46; published online 11 May 2009

Introduction

Nicotine use and dependence is a world-wide health problem. In the United States alone, approximately 45 million people smoke cigarettes and the adverse health effects from cigarette smoking account for an estimated half million deaths each year[1]. Though many cigarette smokers report a desire to quit smoking, few are successful. In fact, according to the US Department of Health and Human Services, approximately 80% of smokers who attempt to quit relapse before achieving 6 months of...