Extracellular recording techniques were used to study antidromically activated nigrostriatal (NSDA) and mesoaccumbens (MADA) dopamine neurons in chloral hydrate-anesthetized rats. Repeated 14-day i.p. treatment with the dopamine D2-like receptor agonists, quinpirole (2 mg/kg/day) or EMD 23448 (2.6 mg/kg/day), resulted in a significant decrease in the average potency and efficacy of i.v. quinpirole (cumulative doses administered on day 15) to inhibit the spontaneous activity of NSDA neurons relative to vehicle controls. Repeated 14-day quinpirole treatment caused a significantly greater decrease in the sensitivity of MADA neurons to i.v. quinpirole challenges than NSDA neurons. When the effects on NSDA neurons were examined after a shorter treatment period, the decrease in the average potency and efficacy of i.v. quinpirole appeared to occur after only 2 days of i.p. quinpirole treatment (2 mg/kg/day). Iontophoretic studies, however, indicated that the average dopamine sensitivity of somatodendritic dopamine autoreceptors on MADA neurons, but not NSDA neurons, was significantly lower relative to controls after 14-day quinpirole treatment (2 mg/kg/day). These results suggest that this quinpirole treatment regimen can differentially affect the average sensitivity of somatodendritic dopamine autoreceptors on MADA and NSDA neurons. The somatodendritic autoreceptors on MADA neurons appear to be more sensitive to the effects of repeated 14-day quinpirole treatment than those on NSDA neurons.