GABA-B RECEPTORS AND PARKINSON'S DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The main goals of this project are: (1) To characterize changes in the localization and function of GABAB receptors in MPTP-treated parkinsonian monkeys and (2) To elucidate the role of GABA transporters in the regulation of GABAB receptor activation in the globus pallidus (GP). Over the past year, two monkeys were rendered parkinsonian with weekly injections of MPTP. We then studied the activity of single neurons in GPe, before, during and after local injection of GABA-B receptor agonist and antagonist or GAT-1 or GAT-3 blockers. The effects of the GABA-B agonist were similar to what we found previously in normal monkeys, that is, a profound decrease in the firing of all GPe neurons tested. In contrast, blockade of GABA-B receptors induced variable responses, most noticeable an increase in firing. A possible way to interpret this unexpected result is that the GABA-B presynaptic receptors are upregulated in parkinsonism so that their blockade produced an increased GABAergic transmission, and a subsequent decrease in firing. The effects obtained with the GATs blockers were different from those observed in normal monkeys, ie both GAT-1 and GAT-3 blockade produced consistent decrease in the cell firing in normal monkeys, while there was often no effect on the firing rate of GPe cells after blockade of GAT-1 and even less after GAT-3 transporter blockade in parkinsonians. Finally, using patch clamp recording method in brain slices, we showed powerful effects of GABA transporter blockade on GABAB-mediated transmission in rat GP neurons, suggesting the importance of non-synaptic GABA spillover in mediating GABAB receptors activation in the GP. Together, these findings provide a solid basis for a deeper understanding of GABAB receptor function in the basal ganglia, and help characterize the potential significance of these receptors as new therapeutic targets for Parkinson's disease.