Intranigral transplants of GABA-rich striatal tissue induce behavioral recovery in the rat Parkinson model and promote the effects obtained by intrastriatal dopaminergic transplants

Intrastriatal transplantation of fetal ventral mesencephalon (VM) is curren tly explored as a potential clinical therapy in Parkinson's disease (PD). A lthough providing substantial benefit for the patient,behavioral recovery s o far obtained with intrastriatal VRI grafts is not complete. Using the B-h ydroxydopamine lesion model of PD, we show here that near-complete restorat ion of the striatal dopamine (DA) innervation can be achieved by multiple i ntrastriatal microtransplants of fetal DA cells; nevertheless, complete rec overy in complex sensorimotor behaviors was not obtained in these animals. In line with the current model of basal ganglia function, this suggests tha t the lesion-induced overactivity of the basal ganglia output structures, i .e., the substantia nigra (SN) and the entopeduncular nucleus, may not be c ompletely reversed by intrastriatal VM grafts. In the present study, we hav e transplanted fetal VM tissue or fetal striatal tissue, as a source of DA and GABA neurons, respectively, into the SN of DA-depleted rats. Intranigra l VRI grafts induced behavioral recovery in some sensorimotor behaviors (fo relimb akinesia and balance tests), but the effect did not exceed the recov ery observed after intrastriatal VM grafts. Intranigral grafts of striatal tissue induced a pattern of functional recovery which was distinctly differ ent from that observed after intranigral VM grafts, and recovery in coordin ated forelimb use in the paw-reaching test was even more pronounced than af ter intrastriatal transplantation of VM cells. Combined transplantation of DA neurons into the striatum and GABA-rich striatal neurons into the SN ind uced additive effects of behavioral recovery observed in the forelimb akine sia test. We propose that intranigral striatal transplants, by a GABA-media ted inhibitory action, can reduce the overactivity of the host SN projectio n 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 f unctional efficacy of intrastriatal VM grafts. (C) 1999 Academic Press.