Review. Neurobiology of nicotine dependence

Philos Trans R Soc Lond B Biol Sci. 2008 Oct 12;363(1507):3159-68. doi: 10.1098/rstb.2008.0095.


Nicotine is a psychoactive ingredient in tobacco that significantly contributes to the harmful tobacco smoking habit. Nicotine dependence is more prevalent than dependence on any other substance. Preclinical research in animal models of the various aspects of nicotine dependence suggests a critical role of glutamate, gamma-aminobutyric acid (GABA), cholinergic and dopamine neurotransmitter interactions in the ventral tegmental area and possibly other brain sites, such as the central nucleus of the amygdala and the prefrontal cortex, in the effects of nicotine. Specifically, decreasing glutamate transmission or increasing GABA transmission with pharmacological manipulations decreased the rewarding effects of nicotine and cue-induced reinstatement of nicotine seeking. Furthermore, early nicotine withdrawal is characterized by decreased function of presynaptic inhibitory metabotropic glutamate 2/3 receptors and increased expression of postsynaptic glutamate receptor subunits in limbic and frontal brain sites, while protracted abstinence may be associated with increased glutamate response to stimuli associated with nicotine administration. Finally, adaptations in nicotinic acetylcholine receptor function are also involved in nicotine dependence. These neuroadaptations probably develop to counteract the decreased glutamate and cholinergic transmission that is hypothesized to characterize early nicotine withdrawal. In conclusion, glutamate, GABA and cholinergic transmission in limbic and frontal brain sites are critically involved in nicotine dependence.

Publication types

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

MeSH terms

  • Humans
  • Neurobiology
  • Neurotransmitter Agents / metabolism*
  • Receptors, Glutamate / metabolism*
  • Receptors, Nicotinic / metabolism*
  • Substance Withdrawal Syndrome / physiopathology*
  • Synapses / physiology*
  • Tobacco Use Disorder / physiopathology*
  • Ventral Tegmental Area / physiology*
  • gamma-Aminobutyric Acid / metabolism


  • Neurotransmitter Agents
  • Receptors, Glutamate
  • Receptors, Nicotinic
  • gamma-Aminobutyric Acid