Chronic treatment with high doses of haloperidol fails to decrease the time course for the development of depolarization inactivation of midbrain dopamine neurons.

Using extracellular single unit recording techniques, we investigated the effects produced by chronic treatment with high doses of haloperidol (CHAL, 5 mg/kg/day, s.c.) on midbrain dopamine (DA) neuronal activity. This regimen of HAL treatment produced a time-dependent reduction in the number of spontaneously active DA neurons. Additionally, this dose regimen induced an irregular firing pattern in many of the remaining active DA neurons in both the ventral tegmental area (A10) and substantia nigra pars compacta (A9) regions. These effects were comparable to those obtained previously in rats treated chronically with lower doses of HAL (0.5 mg/kg/day, s.c.). However, there was a greater decrease in the number of spontaneously active DA cells detected in rats treated with high doses of HAL for three weeks compared to those receiving the low doses. On the other hand, higher doses of apomorphine (200 micrograms/kg, i.v.) were required to reverse both the reduction of DA activity and irregular discharge pattern in rats treated chronically with high doses of HAL. In conclusion, the results of the present study substantiate the view that CHAL-induced depolarization inactivation (DI) of DA neurons is a time-dependent process and chronic treatment with high doses of HAL did not shorten the time course required for the development of DI on the majority of midbrain DA neurons.