Acute and chronic haloperidol treatment: Comparison of effects on nigral dopaminergic cell activity

Abstract

Antipsychotic drugs produce most of their clinical effects, both therapeutic and adversive, in a time-dependent manner which, depending upon the effect, can take days to years to develop. Using extracellular single unit recording and microiontophoretic techniques, we investigated the effect of chronic haloperidol (CHAL) treatment (0.5 mg/kg/day s.c. × 22 d) on nigral dopaminergic (DA) neuronal activity. These effects were compare to those obtained in control animals, animals acutely treated with haloperidol (AHAL), and animals which had been treated for 21 days but not tested until a week after haloperidol had been discontinued (CHAL+l). CHAL treatment resulted in an almost total absence of spontaneously firing nigral DA cells. “Silent” DA cells became active when GABA or DA was applied microiontophoretically but they were unresponsive to glutamic acid. I.V. apomorphine also caused the DA cells to fire. Destruction of nigro-striatal feedback pathways by injection of kainic acid into the caudate nucleus prior to CHAL treatment prevented the disappearance of dopamine cell activity on the lesioned side. In AHAL animals a significantly greater number of spontaneously firing DA cells were found than in controls. In control animals inhibited DA cells could be activated by microiontophoretic glutamic acid or i.v. haloperidol but not by GABA. These results suggest that CHAL treatment causes an increase in the activity of DA cells to the point that the great majority go into apparent tonic depolarization block. This effect appears to be mediated via striato-nigral feedback pathways. AHAL treatment appears to activate DA cells that are normally inactive as well as accelerate the firing rate of spontaneously firing DA neurons. The possible relevance of these findings to the time-dependent neurological side effects induced by haloperidol is discussed.