TY - JOUR
T1 - 1-Methyl-4-phenylpridinium (MPP+)-induced functional run-down of GABAA receptor-mediated currents in acutely dissociated dopaminergic neurons
AU - Wu, Jie
AU - Chan, Piu
AU - Schroeder, Katherine M.
AU - Ellsworth, Kevin
AU - Partridge, L. Donald L.
PY - 2002/10
Y1 - 2002/10
N2 - 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.
AB - 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.
KW - ATP
KW - Dopaminergic neuron
KW - GAGA receptor
KW - MPP
KW - MPTP
KW - Patch-clamp
UR - http://www.scopus.com/inward/record.url?scp=0036788203&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036788203&partnerID=8YFLogxK
U2 - 10.1046/j.1471-4159.2002.01099.x
DO - 10.1046/j.1471-4159.2002.01099.x
M3 - Article
C2 - 12358732
AN - SCOPUS:0036788203
VL - 83
SP - 87
EP - 99
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 1
ER -