The effect of the nicotinic agonist, dimethylphenylpiperazinium (DMPP), to release endogenous dopamine (DA) from striatal slices obtained from animals chronically treated with the nicotinic agonist for 7 or 14 days was determined. Endogenous DA was measured by high pressure liquid chromatography coupled to electrochemical detection. There was no difference in the DMPP concentration-effect curve for DA release from slices obtained from untreated rats or rats treated with saline. Treatment with DMPP for 7 days did not change the DMPP concentration-effect curve when compared to saline treatment. In contrast, treatment of rats with DMPP for 14 days resulted in a significant attenuation of the DMPP-induced release of DA. These studies support the hypothesis that chronic treatment with nicotinic agonists results in a functional uncoupling of cholinergic nicotinic receptors facilitating DA release in the striatum.