The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence

Behav Brain Res. 2000 Aug;113(1-2):73-83. doi: 10.1016/s0166-4328(00)00202-3.


A majority of habitual tobacco smokers find it very difficult to quit the habit because they become addicted to the nicotine present in tobacco smoke. Nicotine, like other psychostimulant drugs of abuse, increases dopamine release in the principal terminal field of the mesolimbic system, the nucleus accumbens, and there is evidence that this mediates the 'rewarding' properties of the drug, which reinforce its self-administration. This review focuses on the working hypothesis that addiction to nicotine, and other psychostimulant drugs, depends upon their ability to evoke a sustained increase in dopamine release directly into the extracellular space which lies between the cells in the nucleus accumbens where it stimulates extra-synaptic dopamine receptors. It is suggested that increased stimulation of these receptors is associated with increased incentive learning or the attribution of increased incentive salience to the cues associated with acquisition and delivery of the drug. The hypothesis proposes that these cues can become conditioned reinforcers of drug-taking behaviour. The receptors, which mediate the effects of nicotine on mesoaccumbens dopamine neurones, are desensitised by sustained exposure to nicotine at concentrations commonly found in the plasma of habitual smokers. It is proposed that, at times when the plasma nicotine concentration is sufficiently high to cause desensitisation of the receptors, tobacco smoking is maintained by the conditioned reinforcers present in the tobacco smoke. The hypothesis predicts, therefore, that conditioned reinforcement may play a more important role in the addiction to tobacco than for most other addictive behaviours. As a result, studies with nicotine have the potential to contribute to our understanding of the neurobiology of addiction which cannot easily be explored using drugs, such as cocaine and amphetamine, which invariably increase dopamine overflow in the forebrain.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Conditioning, Classical / physiology
  • Dopamine / physiology*
  • Extracellular Space / physiology
  • Humans
  • Limbic System / physiopathology*
  • Mesencephalon / physiopathology*
  • Motivation
  • Nucleus Accumbens / physiopathology
  • Synaptic Transmission / physiology*
  • Tobacco Use Disorder / physiopathology*


  • Dopamine