Dopaminergic inhibition of striatal GABA release after 6-hydroxydopamine

We have examined the regulation of striatal GABA release by endogenous dopamine in rats with partial degeneration of dopamine-containing neurons, 6-Hydroxydopamine was administered into the lateral ventricles or medial forebrain bundle. Either 3 days or 3 weeks later, slices of neostriatum were prepared, preloaded with [H-3]GABA, and superfused in order to measure [H-3]GABA overflow in response to electrical stimulation (8 Hz). The loss of dopaminergic terminals was estimated by measuring tissue levels of dopamine. The impact of endogenous dopamine on [H-3]GABA was evaluated by measuring the ability of sulpiride, a D-2 dopamine receptor antagonist, to increase the depolarization-induced [H-3]GABA overflow. In non-treated or vehicle-pretreated rat neostriatum, sulpiride (10 mu M) increased the depolarization-induced [H-3]GABA overflow to 193% of control. Three days after lesioning, the stimulatory effect of sulpiride on [H-3]GABA overflow was identical to that seen in control rats so long as the loss of tissue dopamine did not exceed 60%, although with larger lesions the sulpiride-induced response was reduced. Three weeks after lesioning, however, the stimulatory effect of sulpiride on electrically evoked [H-3]GABA overflow remained at the level seen in control tissue even in cases where tissue dopamine was reduced to 13% of normal. In contrast, no sulpiride-induced increase in [H-3]GABA overflow was detected 3 weeks after nearly complete lesions which reduced tissue dopamine to 2% of normal. These data suggest that short- and long-term compensatory changes maintain dopaminergic control over GABAergic projection neurons and interneurons until the loss of dopamine innervation is almost complete.