1-Methyl-4-Phenylpridinium (Mpp+)-Induced Functional Run-Down Of Gabaa Receptor-Mediated Currents In Acutely Dissociated Dopaminergic Neurons
We have evaluated GABAA receptor function during treatment of 1-methyl-4-phenylpridinium (MPP+) using patch-clamp perforated whole-cell recording techniques in acutely dissociated dopaminergic (DAergic) neurons from rat substantia nigra compacta (SNc). Î³-Aminobutyric acid (GABA), glutamate or glycine induced inward currents (IGABA, IGlu, IGly) at a holding potential (VH) of -45 mV. The IGABA was reversibly blocked by the GABAA receptor antagonist, bicuculline, suggesting that IGABA is mediated through the activation of GABAA receptors. During extracellular perfusion of MPP+ (1-10 Î¼M), but neither IGlu nor IGly, declined (termed run-down) with repetitive agonist applications, indicating that the MPP+-induced IGABA run-down occurred earlier than IGly or IGlu under our experimental conditions. The MPP+-induced IGABA run-down can be prevented by a DA transporter inhibitor, mazindol, and can be mimicked by a metabolic inhibitor, rotenone. Using conventional whole-cell recording with different concentrations of ATP in the pipette solution, IGABA run-down can be induced by decreasing intracellular ATP concentrations, or prevented by supplying intracellular ATP, indicating that IGABA run-down is dependent on intracellular ATP concentrations. A GABAA receptor positive modulator, pentobarbital (PB), potentiated the declined IGABA and eliminated IGABA run-down. Corresponding to these patch-clamp data, tyrosine hydroxylase (TH) immunohistochemical staining showed that TH-positive cell loss was protected by PB during MPP+ perfusion. It is concluded that extracellular perfusion of MPP+ induces a functional run-down of GABAA receptors, which may cause an imbalance of excitation and inhibition of DAergic neurons.
Journal of Neurochemistry
Digital Object Identifier (DOI)
Wu, Jie; Chan, Piu; Schroeder, Katherine M.; Ellsworth, Kevin; and Partridge, L. Donald L., "1-Methyl-4-Phenylpridinium (Mpp+)-Induced Functional Run-Down Of Gabaa Receptor-Mediated Currents In Acutely Dissociated Dopaminergic Neurons" (2002). Neurobiology. 397.