Abstract
In addition to the medium spiny neurons the mammalian striatum contains a small population of GABAergic interneurons that are immunoreactive for tyrosine hydroxylase (TH), which dramatically increases after lesions to the nigrostriatal pathway and striatal delivery of neurotrophic factors. The regulatory effect of levodopa (L-Dopa) on the number and phenotype of these cells is less well understood. Eleven macaques (Macaca fascicularis) were included. Group I (n = 4) received 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and L-Dopa; Group II (n = 4) was treated with MPTP plus vehicle and Group III (n = 3) consist of intact animals (control group). L-Dopa and vehicle were given for 1 year and animals sacrificed 6 months later. Immunohistochemistry against TH was used to identify striatal and nigral dopaminergic cells. Double and triple labeling immunofluorescence was performed to detect the neurochemical characteristics of the striatal TH-ir cells using antibodies against: TH, anti-glutamate decarboxylase (GAD67) anti-calretinin (CR) anti-dopa decarboxylase (DDC) and anti-dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32). The greatest density of TH-ir striatal cells was detected in the striatum of the L-Dopa treated monkeys and particularly in its associative territory. None of the striatal TH-ir cell expressed DARPP-32 indicating they are interneurons. The percentages of TH-ir cells that expressed GAD67 and DDC was approximately 50%. Interestingly, we found that in the L-Dopa group the number of TH/CR expressing cells was significantly reduced. We conclude that chronic L-Dopa administration produced a long-lasting increase in the number of TH-ir cells, even after a washout period of 6 months. L-Dopa also modified the phenotype of these cells with a significant reduction of the TH/CR phenotype in favor of an increased number of TH/GAD cells that do not express CR. We suggest that the increased number of striatal TH-ir cells might be involved in the development of aberrant striatal circuits and the appearance of L-Dopa induced dyskinesias.
Highlights
The striatum is the main afferent structure of the basal ganglia
A marked and significant loss of dopaminergic neurons was observed in the substantia nigra pars compacta (SNpc) of all MPTP-monkeys (40% cell loss approximately)
No significant differences were observed between L-Dopa and vehicle groups, indicating that L-Dopa does not alter the survival of dopaminergic cells in the SNpc (Table 1)
Summary
The striatum is the main afferent structure of the basal ganglia It is primarily composed of GABAergic spiny projection neurons that make up approximately 95% of all the striatal neurons in rodents. A small population of these GABAergic interneurons is immunoreactive for tyrosine hydroxylase (TH-ir), the rate-limiting enzyme in catecholamine synthesis. These TH-ir cells have been preferentially found in the anterior striatum of several species including rat, mouse [4,5,6], monkey [7,8,9,10,11] and human [11,12,13]
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