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

A majority of habitual tobacco smokers find it very difficult to quit the h abit because they become addicted to the nicotine present in tobacco smoke. Nicotine, like other psychostimulant drugs of abuse, increases dopamine re lease in the principal terminal field of the mesolimbic system, the nucleus accumbens, and there is evidence that this mediates the 'rewarding' proper ties of the drug, which reinforce its self-administration. This review focu ses on the working hypothesis that addiction to nicotine, and other psychos timulant 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 dopam ine receptors. It is suggested that increased stimulation of these receptor s is associated with increased incentive learning or the attribution of inc reased incentive salience to the cues associated with acquisition and deliv ery of the drug. The hypothesis proposes that these cues can become conditi oned reinforcers of drug-taking behaviour. The receptors, which mediate the effects of nicotine on mesoaccumbens dopamine neurones, are desensitised b y sustained exposure to nicotine at concentrations commonly found in the pl asma of habitual smokers. It is proposed that, at times when the plasma nic otine concentration is sufficiently high to cause desensitisation of the re ceptors, tobacco smoking is maintained by the conditioned reinforcers prese nt in the tobacco smoke. The hypothesis predicts, therefore, that condition ed reinforcement may play a more important role in the addiction to tobacco than for most other addictive behaviours. As a result, studies with nicoti ne have the potential to contribute to our understanding of the neurobiolog y of addiction which cannot easily be explored using drugs, such as cocaine and amphetamine, which invariably increase dopamine overflow in the forebr ain. (C) 2000 Elsevier Science B.V. All rights reserved.