1-Methyl-4-phenylpridinium (MPP+)-induced functional run-down of GABA(A) receptor-mediated currents in acutely dissociated dopaminergic neurons.
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.
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002469:Cell Separation; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D018756:GABA Antagonists; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000255:Adenosine Triphosphate; D010424:Pentobarbital; D015655:1-Methyl-4-phenylpyridinium; D005998:Glycine; D004298:Dopamine