Electrophysiological, biochemical, and behavioral studies of acute haloperidol-induced depolarization block of nigral dopamine neurons.

The electrophysiological, biochemical and behavioral responses produced by administration of haloperidol were studied in intact rats and in rats with 6-hydroxydopamine-induced partial lesions of the nigrostriatal dopamine pathway. In both control rats and rates tested four to 10 days postlesion, the electrophysiological response of nigral dopamine neurons to increasing doses of haloperidol consisted of either: (1) an increase in firing rate which reached a plateau at six to 10 spikes per second, or (2) no response (i.e., less than 20% change in firing rate). Administration of additional doses of haloperidol up to lethal levels did not elicit further changes in dopamine cell firing in these rats. In contrast, in 6-hydroxydopamine-treated rats tested four to six weeks postlesion, acute administration of haloperidol was not only more consistent in producing increases in dopamine cell firing rate, but also caused six out of seven dopamine neurons tested to cease firing upon entering a state of depolarization block. In all cases in which depolarization block was observed, dopamine cell firing was reinstated by either iontophoretic application of gamma-aminobutyric acid or intravenous administration of apomorphine. In parallel studies, haloperidol caused an increase in the extracellular dopamine levels measured by microdialysis in the striatum of control rats, whereas administration of the same dose of haloperidol to 6-hydroxydopamine-treated rats four to six weeks postlesion did not elicit any change in extracellular dopamine levels. In addition, administration of haloperidol at a dose which was ineffective in control rats produced gross motor deficits in the 6-hydroxydopamine-treated rats when tested four to six weeks postlesion. These results show that 6-hydroxydopamine-induced dopamine depletions produce a time-dependent change in the responsivity of the nigrostriatal dopamine system to acute haloperidol administration. In this altered system, the induction of depolarization block of spike activity in nigral dopamine neurons by haloperidol was not associated with a corresponding decrease in extracellular dopamine levels measured in the striatum. However, it appeared that depolarization block did prevent haloperidol-induced increases in extracellular dopamine levels. The occurrence of depolarization block in the dopamine-depleted animal may limit the capacity of this system to respond to additional compromise, in spite of the compensatory processes that contribute to maintaining motor function.