Mechanism-based medication development for the treatment of nicotine dependence

Abstract

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 alpha4beta2 and alpha7 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.

Figures

Figure 1

Schematic diagram of the mesolimbic dopamine (DA) projection pathway, illustrating the actions of nicotine on extracellular DA, glutamate and GABA in the ventral tegmental area (VTA), and the sites of action of various mechanism-based pharmacological agents in medication development for the treatment of tobacco dependence. The mesolimbic DA system originates in the VTA and projects to the nucleus accumbens (NAc). In the VTA, DA neurons (purple) are under tonic excitatory glutamatergic afferent influence from the medial prefrontal cortex (orange), and tonic inhibitory GABAergic afferent influence from GABAergic interneurons (teal) and also from long-loop GABAergic projections from the NAc (not shown). Nicotine activates mesolimbic DA neurons either via α4β2 nAChRs located on VTA DA and GABAergic neurons or via α7 nAChRs on DA neurons and glutamatergic terminals. Chronic nicotine exposure may also increase endocannabinoid contents in the VTA and NAc, which may remove the tonic inhibitory GABAergic control on VTA DA neurons via CB1 receptors localized on VTA GABAergic neurons or their terminals. Based on this hypothesis, various pharmacological agents that target ACh, DA, glutamate, GABA, and endocannabinoid transmission have been proposed and studied for their potential use in the treatment of tobacco dependence. More details for each class of pharmacological agents are discussed in the text of this review.