Intrastriatal dopaminergic grafts restore inhibitory control over striatal cholinergic neurons

The aim of the study was to examine the influence of intrastriatal dopaminergic grafts on the functioning of striatal cholinergic neurons using an in vitro superfusion method. Rats bearing unilateral 6-hydroxydopamine lesion of the nigrostriatal dopaminergic system received a cell suspension obtained from ED 14 rat embryonic mesencephali which was injected into the denervated striatum. Lesioned animals displayed an ipsilateral rotation in response to amphetamine (5 mg/kg i.p.). This rotational response disappeared following grafting and there was even a significant contralateral rotation in response to the drug. Apomorphine (0.1 mg/kg s.c.) induced a contralateral rotation following the lesion. This latter response was attenuated in the grafted group. Three months after grafting 350 microns thick slices were prepared from striata from the control and experimental sides of lesioned and graft-bearing animals. The slices were preincubated either with 3H-dopamine (10(-7) M) or 3H-choline (10(-7) M) and then superfused with an oxygenated Krebs-Ringer solution. Stimulation with electrical pulses following preincubation with 3H-dopamine elicited a marked increase of tritium outflow from control slices. Stimulation-evoked overflow was of similar magnitude from slices from striata containing the graft, while it was much reduced in slices from lesioned striata. Amphetamine markedly potentiated the effect of electrical stimulation in slices obtained from control and graft-containing striata. Nomifensine (a dopamine uptake blocker) led to a significant decrease of the overflow of 3H-acetylcholine evoked by electrical stimulation from control striatal slices. This inhibition was antagonized by domperidone, a D2 dopamine receptor blocker, a finding which indicates that the action of nomifensine was indeed due to a potentiation of the action of endogenous dopamine released by the electrical stimulation. A similar, although somewhat attenuated, action of nomifensine and domperidone was observed for striatal slices containing the graft. Amphetamine inhibited the stimulation evoked overflow of 3H-acetylcholine in a dose-dependent manner from striatal slices obtained both from the intact and experimental sides of graft-bearing animals, while it had no action on slices from denervated striata. Finally, the dose-response curve for the inhibition of 3H-acetylcholine release by apomorphine was significantly shifted to the left for slices from the lesioned striata as compared with control slices. This leftward shift was totally abolished in the slices from the graft-containing striatum.(ABSTRACT TRUNCATED AT 400 WORDS)