Intrastriatal transplantation of fetal ventral mesencephalon (VM) is currently explored as a potential clinical therapy in Parkinson's disease (PD). Although providing substantial benefit for the patient, behavioral recovery so far obtained with intrastriatal VM grafts is not complete. Using the 6-hydroxydopamine lesion model of PD, we show here that near-complete restoration of the striatal dopamine (DA) innervation can be achieved by multiple intrastriatal microtransplants of fetal DA cells; nevertheless, complete recovery in complex sensorimotor behaviors was not obtained in these animals. In line with the current model of basal ganglia function, this suggests that the lesion-induced overactivity of the basal ganglia output structures, i.e., the substantia nigra (SN) and the entopeduncular nucleus, may not be completely reversed by intrastriatal VM grafts. In the present study, we have transplanted fetal VM tissue or fetal striatal tissue, as a source of DA and GABA neurons, respectively, into the SN of DA-depleted rats. Intranigral VM grafts induced behavioral recovery in some sensorimotor behaviors (forelimb akinesia and balance tests), but the effect did not exceed the recovery observed after intrastriatal VM grafts. Intranigral grafts of striatal tissue induced a pattern of functional recovery which was distinctly different from that observed after intranigral VM grafts, and recovery in coordinated forelimb use in the paw-reaching test was even more pronounced than after intrastriatal transplantation of VM cells. Combined transplantation of DA neurons into the striatum and GABA-rich striatal neurons into the SN induced additive effects of behavioral recovery observed in the forelimb akinesia test. We propose that intranigral striatal transplants, by a GABA-mediated inhibitory action, can reduce the overactivity of the host SN projection neurons and can induce significant recovery in complex motor behavior in the rat PD model and that such grafts may be used to increase the overall functional efficacy of intrastriatal VM grafts.
Copyright 1999 Academic Press.