The "stop" and "go" of nicotine dependence: role of GABA and glutamate

Cold Spring Harb Perspect Med. 2013 Jun 1;3(6):a012146. doi: 10.1101/cshperspect.a012146.


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 γ-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Brain / metabolism
  • Conditioning, Psychological
  • Dopamine / metabolism
  • Excitatory Amino Acid Antagonists / pharmacology
  • GABA Agonists / pharmacology
  • Glutamic Acid / metabolism*
  • Humans
  • Limbic System / metabolism
  • Nicotine / pharmacology
  • Nicotinic Antagonists / pharmacology
  • Receptors, Glutamate / metabolism
  • Reinforcement, Psychology
  • Smoking Cessation
  • Substance Withdrawal Syndrome / metabolism
  • Tobacco Use Disorder / metabolism*
  • Tobacco Use Disorder / psychology
  • gamma-Aminobutyric Acid / metabolism*


  • Excitatory Amino Acid Antagonists
  • GABA Agonists
  • Nicotinic Antagonists
  • Receptors, Glutamate
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Nicotine
  • Dopamine