Fetal Ventral Mesencephalic Grafts Functionally Reduce the Dopamine D2 Receptor Supersensitivity in Partially Dopamine Reinnervated Host Striatum

Abstract

Grafting of ventral mesencephalic tissue in Parkinson's disease results in a partial dopaminergic reinnervation of host brain and dopamine agonist-induced rotational behavior is not completely reversed. To study a possible malfunction of the grafts, extracellular recordings with local applications of quinpirole were utilized and the neurophysiological results showed that a normalization of the upregulated dopamine D2 receptor supersensitivity occurred in reinnervated areas of the host striatum as well as in noninnervated areas remote from the graft innervation. Furthermore, the inhibitory effects on striatal nerve cell firing rate by the D1 receptor agonist SKF 81297 were not different in noninnervated or reinnervated areas of the striatum compared to the control side as seen from the dose–response curves. However, spontaneous striatal neuronal firing was significantly upregulated in noninnervated areas, while it was normalized in areas reached by graft-derived nerve fibers. Dual-probe microdialysis studying potassium-evoked glutamate release revealed that there was no difference in extracellular glutamate levels measured within or lateral to graft dopamine reinnervation. Thus, the upregulated spontaneous activity was not due to a difference in extracellular glutamate levels. The remaining rotational behavior seen after grafting was studied and recordings were performed in the striatum following systemic injection of the D1/D2 agonist apomorphine. The results revealed that apomorphine at the dose used to elicit turning behavior (0.05 mg/kg) still affected striatal neurons in noninnervated areas, while no effect was detected in reinnervated areas and in the intact side. However, a lower dose of apomorphine (0.005 mg/kg) showed no effects on striatal firing in graft reinnervated striata but only after dopamine depletion. In conclusion, the D2 supersensitivity is downregulated in graft-reinnervated striatum as well as in striatal areas lateral to the reinnervation when using selective D2 agonists, but the downregulation is not completely normalized when studying combined effects of D1/D2 agonists. Furthermore, the striatal neurons were firing significantly faster in noninnervated areas compared to reinnervated areas of graft-reinnervated striatum, which was most likely not due to changes in the glutamatergic input.