Time-course of recovery of dopamine neuron activity during reinnervation of the denervated striatum by fetal mesencephalic grafts as assessed by in vivo voltammetry

Summary In vivo voltammetry was used to monitor dopamine (DA) neuron activity during the course of reinnervation of the initially denervated caudateputamen by grafted mesencephalic neurons. Fetal DA neurons were implanted as a cell suspension into the depth of the caudate-putamen in adult 6-hydroxydopamine-lesioned recipient rats. Recordings were performed over a period of 2.5–4 months, starting within a week after transplantation, using chronically implanted surface-treated multifiber carbon electrodes. The voltammetric method used in this study has generated considerable discussion centred on the ability of the multifiber electrodes to measure DA alone in vivo, but the results of previous studies have led to the conclusion that changes in the voltammetric signal most probably reflect dopaminergic terminal activity. It seems therefore possible to follow the time-course of changes in the voltammetric signal amplitude during the process of dopaminergic reinnervation of the host striatum from the grafts. A 6-hydroxydopamine lesion of the mesostriatal dopamine pathway caused a substantial (> 80%) reduction of the voltammetric signal within 8–10 days, and the low residual signal remained essentially unchanged for time periods up to at least 5 months in the non-grafted control rats. In 7 of 11 rats with DA-rich grafts there was a recovery of the signal amplitude to levels within, or close to, the range recorded from the striatum of normal intact rats. The increase was observed 6–8 weeks after grafting in the rats which had received the largest transplants, and at about 13–14 weeks after grafting in the rats which had received the smallest ones. The recovery of the signal amplitude, from baseline to maximal response, was quite rapid and typically developed between two or three recording sessions, i.e. over a period of one to two weeks. In contrast to the intact striatum, the recovered signal in the graft-reinnervated striata showed a progressive decline within one hour of sampling time at high sampling frequencies (1 per min to 1 per 3 min). Grafted striata also showed a larger response to systemically administered amphetamine than did intact striata. Since the changes in the voltammetric signal recorded with the multifiber electrode mainly reflect dopaminergic terminal activity, the results provide evidence that the intrastriatal DA-rich grafts are spontaneously active, and that the grafted DA neurons can restore DA neuro-transmission in the reinnervated part of the host caudate-putamen to levels which are within the normal range. From the time-course of changes in the voltammetric signal it can be estimated that the outgrowing DA fibers, after an initial maturation period, expand from the graft into the host striatum at a maximum rate of about 0.1 mm per week, and that the advancing front of graft-derived fibers may be capable of saturating the area around the electrode tip with new terminals within a time period of about 1–2 weeks. The characteristics of the signal seem compatible with the view that the activity of the individual grafted DA neurons is greater than that of the mesostriatal DA neurons in situ.