Premium
1‐Methyl‐4‐phenylpridinium (MPP + )‐induced functional run‐down of GABA A receptor‐mediated currents in acutely dissociated dopaminergic neurons
Author(s) -
Wu Jie,
Chan Piu,
Schroeder Katherine M.,
Ellsworth Kevin,
Partridge L. Donald L.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.01099.x
Subject(s) - bicuculline , substantia nigra , chemistry , glutamate receptor , gamma aminobutyric acid , gabaergic , dopaminergic , extracellular , gabaa receptor , intracellular , reversal potential , gaba receptor antagonist , receptor , patch clamp , biophysics , medicine , endocrinology , biology , biochemistry , dopamine
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). γ‐Aminobutyric acid (GABA), glutamate or glycine induced inward currents ( I GABA , I Glu , I Gly ) at a holding potential ( V H ) 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 μ m ), 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.