The "Stop" and "Go" of Nicotine Dependence: Role of GABA and Glutamate

Abstract

Nicotine plays an important role in the initiation and maintenance of tobacco smoking. Importantly, chronic nicotine exposure alters the function of brain reward systems, resulting in the development of a nicotine-dependent state. This nicotine-dependent state is associated with aversive affective and somatic signs upon abstinence from smoking, often leading to relapse in abstinent smokers. This article reviews the role of the major excitatory and inhibitory neurotransmitters glutamate and g-aminobutyric acid (GABA), respectively, in both the reinforcing effects of nicotine and development of nicotine dependence. Evidence suggests that blockade of glutamatergic neurotransmission attenuates both nicotine intake and nicotine seeking. In contrast, both nicotine intake and nicotine seeking are attenuated when GABA neurotransmission is facilitated. In conclusion, medications that either attenuate/ negatively modulate glutamatergic neurotransmission or facilitate/positively modulate GABA neurotransmission may be useful for promoting smoking cessation in humans.

Gene-gene interaction of μ-opioid receptor and GluR5 kainate receptor subunit is associated with smoking behavior in a Greek population: presence of a dose allele effect

“…Glutaminergic neurotransmission is also implicated in the mechanism of nicotine dependence [9]. Accumulated findings indicate that the glutaminergic system is indirectly involved in the reward system by increasing dopaminergic excitability [10].…”

Quantifying absolute glutamate concentrations in nucleus accumbens of prescription opioid addicts by using 1H MRS

“…Nevertheless, some animal studies have shown that the administration of nicotine increases glutamate levels in various brain regions (Gass & Olive, 2008). Microdialysis studies suggest that nicotine increases glutamate release in both the VTA and NAc (D'Souza & Markou, 2013;Fu, Matta, Gao, Brower, & Sharp, 2000;Reid et al, 2000). Upregulation of ionotropic glutamate subunits in the prefrontal cortex and the VTA, but not in the NAc, has been reported in chronically nicotine self-administering rats.…”

Investigating Sex-Specific Characteristics of Nicotine Addiction Using Metabolic and Structural Magnetic Resonance Imaging

“…Studies on smokers have indicated the role of glutamate and GABA, in both the reinforcing effects of nicotine and the development of nicotine dependence [25]. Chronic nicotine exposure facilitates glutamate neurotransmission and repeated exposure attenuates GABA neurotransmission in two key regions of reward processing, namely, ventral tegmental area and nucleus accumbens.…”

“…These studies have shown that glutamate serves as a mediator for smokingassociated reward-seeking behaviours. GABA is the major inhibitory neurotransmitter and plays an important role in regulating mesolimbic dopaminergic neurons, which partially mediates the reinforcing effects of nicotine [25]. Facilitation of GABA neurotransmission mediates the smoking cessation.…”

“…Chronic nicotine exposure facilitates glutamate neurotransmission and repeated exposure attenuates GABA neurotransmission in two key regions of reward processing, namely, ventral tegmental area and nucleus accumbens. These two nuclei are known to produce the positive reinforcing and rewarding/motivational effects of nicotine [25][26][27]. Considering this, investigation of the underlying excitatory (glutamate) and inhibitory (GABA) neurotransmission (which mediates nicotine addiction), in females as compared to males, is needed to understand the sex-specific characteristics of nicotine addiction.…”