Involvement of glutamatergic and GABAergic systems in nicotine dependence: Implications for novel pharmacotherapies for smoking cessation - PubMed (original) (raw)

Review

Involvement of glutamatergic and GABAergic systems in nicotine dependence: Implications for novel pharmacotherapies for smoking cessation

Xia Li et al. Neuropharmacology. 2014 Jan.

Abstract

Tobacco smoking continues to be a major global health hazard despite significant public awareness of its harmful consequences. Although several treatment options are currently available for smoking cessation, these medications are effective in only a small subset of smokers, and relapse rates continue to be high. Therefore, a better understanding of the neurobiological mechanisms that mediate tobacco dependence is essential for the development of effective smoking cessation medications. Nicotine is the primary psychoactive component of tobacco that drives the harmful tobacco smoking habit. Nicotine binds to nicotinic acetylcholine receptors (nAChRs) in the brain, resulting in the release of a wide range of neurotransmitters, including glutamate and γ-aminobutyric acid (GABA). This review article focuses on the role of the excitatory glutamate system and inhibitory GABA system in nicotine dependence. Accumulating evidence suggests that blockade of glutamatergic transmission or facilitation of GABAergic transmission attenuates the positive reinforcing and incentive motivational aspects of nicotine, inhibits the reward-enhancing and conditioned rewarding effects of nicotine, and blocks nicotine-seeking behavior. Chronic nicotine exposure produced long-term neuroadaptations that contribute to nicotine withdrawal, but the role of GABA and glutamate transmission in nicotine withdrawal is less understood. Overall, the findings presented in this review provide strong converging evidence for the potential effectiveness of glutamatergic and GABAergic medications in nicotine dependence. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Keywords: Glutamate; Nicotine; Reinforcement; Reinstatement; Withdrawal; γ-aminobutyric acid.

Copyright © 2013 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1

Glutamate, GABA and dopamine interactions that are involved in the development of nicotine dependence. Nicotine binds to excitatory nicotinic acetylcholine receptors (not shown in figure) that are located throughout the brain as auto- or heteroreceptors at presynaptic terminals that regulate the release of several neurotransmitters, including dopamine, glutamate and γ-aminobutyric acid (GABA). The mesolimbic dopaminergic neurons (depicted as yellow lines) mediate the reinforcing effects of several drugs of abuse including nicotine. These dopaminergic neurons originate in the ventral tegmental area and project to several limbic and cortical regions, including the nucleus accumbens, prefrontal cortex, amygdala, hippocampus, and habenula. The activity of these dopaminergic neurons is regulated by reciprocal glutamatergic (excitatory; depicted as blue) and GABAergic (inhibitory; depicted as red lines) projections that originate from the aforementioned cortical and limbic brain regions. AMY, amygdala; LHb, lateral habenula; HC, hippocampus; NAc, nucleus accumbens; PFC, prefrontal cortex; RN, raphe nucleus; VP, ventral pallidum; VTA, ventral tegmental area. Taken with permission from D'Souza MS and Markou A (2012)The “Stop” & “Go” of Nicotine Dependence: Role of GABA and glutamate. In: Addiction: A neurobiological perspective. Pierce, R.C., Kenny, P.J. (eds.). © Cold Spring Harbor Laboratory Press, New York.

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