Differential nicotinic regulation of the nigrostriatal and mesolimbic dopaminergic pathways: implications for drug development

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) modulate dopaminergic function. Discovery of their multiplicity has lead to the search for subtype-selective nAChR agonists that might be therapeutically beneficial in diseases linked to brain dopaminergic pathways. The regulation and responses of the nigrostriatal and mesolimbic dopaminergic pathways are often similar, but some differences do exist. The cerebral distribution and characteristics of various nAChR subtypes differ between nigrostriatal and mesolimbic dopaminergic pathways. Comparison of nicotine and epibatidine, two nAChR agonists whose relative affinities for various nAChR subtypes differ, revealed differences in the nAChR-mediated regulation of dopaminergic activation between these dopamine systems. Nicotine preferentially stimulates the mesolimbic pathway, whereas epibatidine's stimulatory effect falls on the nigrostriatal pathway. Thus, it may be possible to stimulate the nigrostriatal pathway with selective nAChR agonists that do not significantly affect the mesolimbic pathway, and thus lack addictive properties. Furthermore, dopamine uptake inhibition revealed a novel inhibitory effect of epibatidine on accumbal dopamine release, which could form a basis for novel antipsychotics that could alleviate the elevated accumbal dopaminergic tone found in schizophrenia during the active psychotic state. Different regulation of nigrostriatal and mesolimbic dopaminergic pathways by nAChRs could be an important basis for developing novel drugs for treatment of Parkinson's disease and schizophrenia.