INTRANIGRAL FETAL DOPAMINE GRAFTS INDUCE BEHAVIORAL COMPENSATION IN THE RAT PARKINSON MODEL

Neural transplantation in experimental Parkinsonism has so far focused on the ectopic placement of fetal ventral mesencephalic (VM) neurons into the dopamine-denervated caudate-putamen. VM grafts are effective in restoring dopamine neurotransmission in the grafted caudate-putamen and in partial amelioration of behavioral deficits. Recent pharmacolo gical and physiological data have provided strong evidence that dopami ne released from dendrites of the substantia nigra pars compacta (SNc) neurons within the pars reticulata (SNr) prays an important role in t he regulation of the basal ganglia output pathways. Using a novel micr otransplantation approach, multiple small cell suspension grafts (250 nl) derived from the VM of E14 rat embryos were implanted into the SNr of unilaterally 6-hydroxydopamine-lesioned rats. Behavioral changes i n drug-induced rotation asymmetry were monitored for up to 14 weeks po stgrafting, followed by a quantitative assessment and correlation of t yrosine hydroxylase (TH)-positive cell survival. The reduction in rota tional asymmetry caused by the intranigral VM grafts was 64% for SKF 3 8393 (D1 agonist), 54% for apomorphine (mixed D1 and D2 agonist), and 67% for quinpirole (D2 agonist) when compared to a control spinal cord graft group. By contrast, amphetamine-induced rotation was completely unaffected. The correlation between number of TH-positive cells and b ehavioral compensation was highest for the D1 agonist (R = -0.729), th ough clear-cut also for the mixed D1/D2 agonist apomorphine (R = -0.66 4) and the D2 agonist quinpirole (R = -0.642). Favorable morphological features of the VM micrografts included extensive migration of the do paminergic neurons into the host SNr and the formation of dense patche s of dendrite-like TH-positive terminal networks within the SNr. The r esults demonstrate a novel pattern of behavioral recovery induced by i ntranigral VM transplants in the rat Parkinson model. This may have im portant implications for the understanding of how the nigrostriatal do pamine system influences motor control in the basal ganglia as well as for the development of optimal transplantation strategies in Parkinso n's disease.