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Wu J, Chan P, Schroeder KM, Ellsworth K, Partridge LD: 1-Methyl-4-phenylpridinium (MPP+)-induced functional run-down of GABA (A) receptor-mediated currents in acutely dissociated dopaminergic neurons. J Neurochem. 2002 Oct;83(1):87-99.
We have evaluated GABA (A) 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). Gamma-aminobutyric acid (GABA), glutamate or glycine induced inward currents (I (GABA), I (Glu), I (Gly)) at a holding potential (VH) of -45 mV. The I (GABA) was reversibly blocked by the GABA (A) receptor antagonist, bicuculline, suggesting that I (GABA) is mediated through the activation of GABA (A) receptors. During extracellular perfusion of MPP+ (1-10 microm), I (GABA) , but neither I (Glu) nor I (Gly), declined (termed run-down) with repetitive agonist applications, indicating that the MPP+-induced I (GABA) run-down occurred earlier than I (Gly) or I (Glu) under our experimental conditions. The MPP+-induced I (GABA) 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, I (GABA) run-down can be induced by decreasing intracellular ATP concentrations, or prevented by supplying intracellular ATP, indicating that I (GABA) run-down is dependent on intracellular ATP concentrations. A GABA (A) receptor positive modulator, pentobarbital (PB), potentiated the declined I (GABA) and eliminated I (GABA) 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 GABA (A) receptors, which may cause an imbalance of excitation and inhibition of DAergic neurons. |
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