Dopamine (DA) released by substantia nigra pars compacta (SNc) neurons is a key regulator of motor activity. A deficiency in the striatum DA content due to SNc degeneration is a characteristic of Parkinson's disease. The involvement of excitotoxic mechanisms in this pathology has been suggested. The kainate receptor subunit GluR5 has been identified in a few basal ganglia but it is strongly expressed in SNc. Here we examine whether (RS)-2-amino-3-(3-hydroxy-5-tbutylisoxazol-4-yl) propanoic acid (ATPA), a selective agonist of GluR5, induces damage in dopaminergic (DAergic) neurons. ATPA (13 nmol) was administered to rat SNc. Immediately after recovery from surgery, the rats displayed ipsilateral turning. This behavior disappeared in subsequent days. The administration of the D1/D2 agonist, apomorphine (1 mg/kg, s.c.) 1 and 2 weeks after ATPA-infusion also induced ipsilateral turning. Histological studies-performed 21 days after ATPA-infusion-showed a lesion of the lateral and central part of the SNc, where a significant loss (36%) of DAergic cells was detected by tyrosine hydroxylase immunohistochemistry. The lesion was restricted to the SNc, since no damage or glial reaction was observed in the substantia nigra pars reticulata as assessed by Nissl staining, tomato lectin staining for microglial cells and GFAP immunohistochemistry for astrocytes.
In conclusion: (1). ATPA-infusion induces neuronal damage in the SNc in the rat and (2). the behavioral effects of unilateral infusion of ATPA are consistent with DAergic alterations in basal ganglia.