1-Methyl-4-phenylpridinium (MPP+)-induced functional run-down of GABAA receptor-mediated currents in acutely dissociated dopaminergic neurons

Jie Wu, Piu Chan, Katherine M. Schroeder, Kevin Ellsworth, L. Donald L. Partridge

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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). γ-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 μM), 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.

Original languageEnglish (US)
Pages (from-to)87-99
Number of pages13
JournalJournal of neurochemistry
Volume83
Issue number1
DOIs
StatePublished - Oct 2002
Externally publishedYes

Keywords

  • ATP
  • Dopaminergic neuron
  • GAGA receptor
  • MPP
  • MPTP
  • Patch-clamp

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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