Accumulating evidence indicates that nicotinic receptors play a role in basal ganglia function. Furthermore, nicotine administration may be neuroprotective in animal models of nigrostriatal degeneration, while cigarette smoking is inversely correlated with Parkinson's disease. Because nicotinic receptors are decreased in Parkinson's disease, these observations may suggest that nicotinic agonists are beneficial in this disorder. We used two model systems to investigate this possibility. One involved non-human primates, which represent a good model because their neuroanatomical organization resembles that of man and nigrostriatal degeneration leads to biochemical and behavioral deficits similar to Parkinson's disease. To identify the subunits that comprise basal ganglia nicotinic receptors, we investigated alpha4, alpha6, alpha7, beta2, beta3 and beta4 transcript distribution in monkey substantia nigra. All mRNAs were expressed with a selective alteration in some transcripts after 1-methyl-4-phenyl-1,2,3,6-tetrahydropteridine (MPTP) induced nigrostriatal degeneration. As an approach to evaluate neuroprotective effects of nicotine against nigral neuron damage, we used mesencephalic neurons in culture, treated with a selective dopaminergic neurotoxin. The results show that nicotine pretreatment protected against dopaminergic nigral neural degeneration. These data suggest that nicotinic receptor ligands may be useful in Parkinson's disease therapy.