Nicotine dependence--mechanisms and therapeutic strategies

The current view among most researchers and clinicians is that habitual cigarette smoking is a form of dependence on nicotine. It is the central actions of nicotine that appear to be particularly important in this regard. Although multiple subtypes of nicotine receptor are expressed in the brain, attention has focused on a prevalent subtype (containing alpha 4 and beta 2 subunits) which is believed to represent the prime target for 'smoking doses' of nicotine. The mesolimbic dopamine system, a neuronal population which has been implicated in the reinforcing actions of certain drugs (e.g. amphetamine), also appears to mediate the reinforcing actions of nicotine in laboratory rats. Current pharmacotherapeutic approaches to smoking cessation rely on nicotine replacement. It is argued that the administration of a selective antagonist of central nervous system nicotine receptors (Fig. 1) may lead to higher long-term abstinence rates, and research strategies for the development of such a drug are outlined.