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

Abstract

In vivo voltammetry was used to monitor dopamine (DA) neuron activity during the course of reinnervation of the initially denervated caudate-putamen by grafted mesencephalic neurons. Fetal DA neurons were implanted as a cell suspension into the depth of the caudate-putamen in adult 6-hydroxy-dopamine-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 (greater than 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.(ABSTRACT TRUNCATED AT 400 WORDS)

Serotonin Neuron Transplants Exacerbate l-DOPA- Induced Dyskinesias in a Rat Model of Parkinson's Disease

“…The DA neuroncontaining grafts induced a significant (56 -59%) reduction of L-DOPA-induced dyskinesia that developed gradually over the first 10 weeks after transplantation. The time course matched well the progressive development of a functional graft-derived DAterminal network in the striatum (Forni et al, 1989;Brundin et al, 1994). None of these effects was seen in the rats that received 5-HT grafts (i.e., grafts containing large numbers of serotonin neurons but no or only single TH-positive cells).…”

Delayed recovery of movement-related cortical function in Parkinson's disease after striatal dopaminergic grafts

“…In both the rat and marmoset PD models, the development of the capacity for dopamine synthesis and storage in grafts precedes the more gradual improvements in complex sensorimotor behavior by several months. 35,36 The establishment of a new dopaminestoring terminal network in the host striatum is closely correlated to the onset of graft-derived dopamine release 37 and reversal of dopamine receptor supersensitivity in the rat PD model. 36,38 These early effects may all be mediated by tonic nonregulated release of dopamine from spontaneously active grafted neurones.…”

Enhancement of Sensorimotor Behavioral Recovery in Hemiparkinsonian Rats with Intrastriatal, Intranigral, and Intrasubthalamic Nucleus Dopaminergic Transplants

“…As has been shown in a previous study (Mendez et al, 1996), grafting both the SN and ST produces overcompensation with contralateral rotations by 6 weeks after transplantation. Although the mechanism of this overcompensation is not clear, it has been suggested that amphetamine-dependent dopamine release is higher in the transplant side than in the contralateral intact side (Forni et al, 1989).…”