POLYSYNAPTIC REGULATION OF GLUTAMATE RECEPTORS AND MITOCHONDRIAL ENZYME-ACTIVITIES IN THE BASAL GANGLIA OF RATS WITH UNILATERAL DOPAMINE DEPLETION

After nigrostriatal dopaminergic denervation, the output nuclei of the basal ganglia, the medial globus pallidus and substantia nigra pars r eticulata (Snr), become overactive, in part, because of increased acti vity of excitatory afferents from the subthalamic nucleus (STN). Becau se STN uses glutamate as a transmitter, we examined whether there are regulatory changes in glutamate receptor binding in the basal ganglia. Rats received unilateral 6-hydroxydopamine lesions of the medial fore brain bundle and substantia nigra pars compacta that were confirmed by apomorphine-induced rotation and H-3-GBR-12935 binding. As an indirec t index of relative synaptic activity, succinate dehydrogenase and cyt ochrome oxidase activities were assayed histochemically in sections ad jacent to those used for receptor binding. There were increases in enz ymatic activity in entopeduncular nucleus (EP; the rodent homolog of m edial globus pallidus), SNr, and globus pallidus (GP, the rodent homol og of lateral globus pallidus) in the lesioned hemisphere, suggesting increased synaptic activity, perhaps due to increased firing of the ST N. Ipsilateral to the lesion, and postsynaptic to the STN, there were profound decreases in the binding of H-3-AMPA (alpha-amino-3-hydroxy-5 -methylisoxazole propionic acid) in EP and SNr (45% and 30%, respectiv ely); there were no alterations in the striatum, globus pallidus, or S TN, and binding throughout the unlesioned hemisphere was equivalent to that in unlesioned control animals. In contrast, H-3-MK-801 binding t o the NMDA receptor ion channel was not reduced in SNr, and was too lo w to be measured reliably in EP and STN. H-3-MK-801 binding was reduce d by 6% in striatum and 39% in globus pallidus. Compared to animals th at did not receive lesions, there were >30% bilateral reductions in st riatal binding, which were larger ipsilateral to the lesion. Our resul ts suggest that the alterations in basal ganglia circuitry associated with nigrostriatal dopamine depletion are reflected in (1) changes in succinate dehydrogenase and cytochrome oxidase activities, (2) downreg ulation of AMPA receptors in EP and SNr, and (3) bilateral reductions in striatal NMDA receptors.