Pharmacological evidence for feedback regulation of dopamine metabolism in solid fetal substantia nigra transplants.

Solid grafts of fetal ventral mesencephalic tissue transplanted into a cavity overlying a dopamine (DA)-deafferented striatum are known to survive, send terminals into the host striatum and release DA. Using this preparation, we have examined receptor-mediated feedback modulation of DA metabolism in the graft and, separately, in its terminals in the host striatum. For this purpose we administered the DA receptor antagonist, haloperidol, and the DA receptor agonist, apomorphine (APO), systemically, and calculated the dihydroxyphenylacetic acid/DA and homovanillic acid/DA ratios as an index of DA turnover in the graft itself as well as in the adjacent host striatum. A marked increase in dihydroxyphenylacetic acid/DA and homovanillic acid/DA ratios was seen after haloperidol treatment. This increase was found 1) within the solid transplant tissue itself as well as 2) within the transplant reinnervated regions of the host striatum. The net elevation in DA metabolites associated with the transplant terminals was less than that obtained in the intact striatum. APO significantly decreased the dihydroxyphenylacetic acid/DA and homovanillic acid/DA ratios in the transplant-innervated regions of the host striatum; this effect of APO was of a greater magnitude than that seen in intact controls. Within the solid transplant itself, APO caused slight but not significant decreases in DA metabolism. Our findings demonstrate that the transplanted DA neurons are subject to negative feedback regulation mediated via DA receptors and that transplant DA utilization is subject to both increases and decreases in response to drug-induced manipulations of DA receptors.