Serotonin-dopamine interaction in nicotine addiction: Focus on 5-HT_2C receptors

Central dopaminergic systems play a critical role in the regulation of normal and abnormal behaviors. Recent evidence suggests that a dysfunction of dopamine (DA) and serotonin (5-HT) neurotransmitter systems contribute to various pathological conditions. Substantial evidence indicates that the mesolimbic pathway, particularly the DA cells innervating accumbal areas, is implicated in the reward value of both natural and drug reinforcers, such as sexual behavior or psychostimulants, respectively. Nicotine, the major psychoactive agent present in tobacco, acts as a potent addictive drug both in humans and laboratory animals. The locomotor activation and the reinforcing effects of nicotine may be related to its stimulatory effects on the mesolimbic dopaminergic function. Thus, it is now well established that nicotine can increase in vivo DA outflow in the nucleus accumbens and the corpus striatum. The stimulatory effect of nicotine on DA release most probably results from its ability to excite neuronal firing rate and to increase bursting activity of DA neurons within the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), together with its facilitatory activity on DA terminal release in the corpus striatum and the nucleus accumbens. The neurochemical data are consistent with neuroanatomical findings showing the presence of nicotinic acetylcholine receptors (nAChRs) in the SNc, VTA, and in projection areas of the central dopaminergic system such as the corpus striatum and the nucleus accumbens. Several lines of evidence indicate that the reinforcing properties of drugs of abuse, including nicotine, can be affected by the serotonergic system which may act by modulating central dopaminergic function. In this paper, the effects of 5-HT2C receptors on DA function in relation to the neurobiological mechanisms underlying nicotine addiction will be reviewed, and the possible strategies with 5-HT2C agents for new pharmacological treatments of nicotine dependence will be examined.