Potentiation of GABAA receptor agonists by GABA uptake inhibitors in the rat ventral midbrain

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Abstract

Whole-cell patch recordings were made from dopamine-containing neurons in the ventral tegmental area (VTA) and substantia nigra zona compacta (SNC). Isoguvacine evoked an outward current (at -60 mV) in a concentration-dependent manner with an EC50 of 62 ± 8 μM. The γ-aminobutyric acid (GABA) uptake inhibitor 1-(2(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridine- carboxylic acid hydrochloride (NO 711) (3 μM) shifted the isoguvacine concentration-response curve to the left, with a new EC50 of 22 ± 4 μM. L-Arginine (3 mM) also shifted the isoguvacine concentration-response curve to the left, with a new EC50 of 29 ± 5 μM. L-Arginine (3 mM) increased the currents evoked by GABA (100 μM) and muscimol (1 μM) by 208% and 261%, respectively. The GABA uptake inhibitor 4,5,6,7,-tetrahydroisoxazolo[4,5-c]-pyridin-3-ol hydrobromide (THPO) (300 μM) not only mimicked but also occluded the ability of L-arginine (3 mM) to potentiate currents evoked by isoguvacine. Equimolar replacement of Na+ with choline increased GABA-evoked currents, suggesting that a low Na+ concentration has an inhibitory effect on GABA transport. Low Na+ concentration (25 mM) inhibited isoguvacine currents but still occluded the potentiating effects of L-arginine. We conclude that GABA uptake inhibitors potentiate the actions of the GABAA receptor agonists, isoguvacine and muscimol, probably because they are effective substrates for GABA transporters in the ventral midbrain.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalEuropean Journal of Pharmacology
Volume428
Issue number1
DOIs
StatePublished - Sep 28 2001

Fingerprint

GABA Uptake Inhibitors
GABA-A Receptor Agonists
Mesencephalon
Arginine
gamma-Aminobutyric Acid
Muscimol
GABA Plasma Membrane Transport Proteins
Aminobutyrates
Ventral Tegmental Area
Dopaminergic Neurons
Herpes Zoster
Patch-Clamp Techniques
Carboxylic Acids
Choline
isoguvacine

Keywords

  • γ-Aminobutyric acid (GABA) transporter
  • Dopamine neuron
  • Isoguvacine
  • L-Arginine
  • Muscimol
  • NO 711

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

@article{905422f226ab4d90a1e4fed5d6455922,
title = "Potentiation of GABAA receptor agonists by GABA uptake inhibitors in the rat ventral midbrain",
abstract = "Whole-cell patch recordings were made from dopamine-containing neurons in the ventral tegmental area (VTA) and substantia nigra zona compacta (SNC). Isoguvacine evoked an outward current (at -60 mV) in a concentration-dependent manner with an EC50 of 62 ± 8 μM. The γ-aminobutyric acid (GABA) uptake inhibitor 1-(2(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridine- carboxylic acid hydrochloride (NO 711) (3 μM) shifted the isoguvacine concentration-response curve to the left, with a new EC50 of 22 ± 4 μM. L-Arginine (3 mM) also shifted the isoguvacine concentration-response curve to the left, with a new EC50 of 29 ± 5 μM. L-Arginine (3 mM) increased the currents evoked by GABA (100 μM) and muscimol (1 μM) by 208{\%} and 261{\%}, respectively. The GABA uptake inhibitor 4,5,6,7,-tetrahydroisoxazolo[4,5-c]-pyridin-3-ol hydrobromide (THPO) (300 μM) not only mimicked but also occluded the ability of L-arginine (3 mM) to potentiate currents evoked by isoguvacine. Equimolar replacement of Na+ with choline increased GABA-evoked currents, suggesting that a low Na+ concentration has an inhibitory effect on GABA transport. Low Na+ concentration (25 mM) inhibited isoguvacine currents but still occluded the potentiating effects of L-arginine. We conclude that GABA uptake inhibitors potentiate the actions of the GABAA receptor agonists, isoguvacine and muscimol, probably because they are effective substrates for GABA transporters in the ventral midbrain.",
keywords = "γ-Aminobutyric acid (GABA) transporter, Dopamine neuron, Isoguvacine, L-Arginine, Muscimol, NO 711",
author = "Ke-Zhong Shen and Steven Johnson",
year = "2001",
month = "9",
day = "28",
doi = "10.1016/S0014-2999(01)01218-3",
language = "English (US)",
volume = "428",
pages = "1--7",
journal = "European Journal of Pharmacology",
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T1 - Potentiation of GABAA receptor agonists by GABA uptake inhibitors in the rat ventral midbrain

AU - Shen, Ke-Zhong

AU - Johnson, Steven

PY - 2001/9/28

Y1 - 2001/9/28

N2 - Whole-cell patch recordings were made from dopamine-containing neurons in the ventral tegmental area (VTA) and substantia nigra zona compacta (SNC). Isoguvacine evoked an outward current (at -60 mV) in a concentration-dependent manner with an EC50 of 62 ± 8 μM. The γ-aminobutyric acid (GABA) uptake inhibitor 1-(2(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridine- carboxylic acid hydrochloride (NO 711) (3 μM) shifted the isoguvacine concentration-response curve to the left, with a new EC50 of 22 ± 4 μM. L-Arginine (3 mM) also shifted the isoguvacine concentration-response curve to the left, with a new EC50 of 29 ± 5 μM. L-Arginine (3 mM) increased the currents evoked by GABA (100 μM) and muscimol (1 μM) by 208% and 261%, respectively. The GABA uptake inhibitor 4,5,6,7,-tetrahydroisoxazolo[4,5-c]-pyridin-3-ol hydrobromide (THPO) (300 μM) not only mimicked but also occluded the ability of L-arginine (3 mM) to potentiate currents evoked by isoguvacine. Equimolar replacement of Na+ with choline increased GABA-evoked currents, suggesting that a low Na+ concentration has an inhibitory effect on GABA transport. Low Na+ concentration (25 mM) inhibited isoguvacine currents but still occluded the potentiating effects of L-arginine. We conclude that GABA uptake inhibitors potentiate the actions of the GABAA receptor agonists, isoguvacine and muscimol, probably because they are effective substrates for GABA transporters in the ventral midbrain.

AB - Whole-cell patch recordings were made from dopamine-containing neurons in the ventral tegmental area (VTA) and substantia nigra zona compacta (SNC). Isoguvacine evoked an outward current (at -60 mV) in a concentration-dependent manner with an EC50 of 62 ± 8 μM. The γ-aminobutyric acid (GABA) uptake inhibitor 1-(2(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridine- carboxylic acid hydrochloride (NO 711) (3 μM) shifted the isoguvacine concentration-response curve to the left, with a new EC50 of 22 ± 4 μM. L-Arginine (3 mM) also shifted the isoguvacine concentration-response curve to the left, with a new EC50 of 29 ± 5 μM. L-Arginine (3 mM) increased the currents evoked by GABA (100 μM) and muscimol (1 μM) by 208% and 261%, respectively. The GABA uptake inhibitor 4,5,6,7,-tetrahydroisoxazolo[4,5-c]-pyridin-3-ol hydrobromide (THPO) (300 μM) not only mimicked but also occluded the ability of L-arginine (3 mM) to potentiate currents evoked by isoguvacine. Equimolar replacement of Na+ with choline increased GABA-evoked currents, suggesting that a low Na+ concentration has an inhibitory effect on GABA transport. Low Na+ concentration (25 mM) inhibited isoguvacine currents but still occluded the potentiating effects of L-arginine. We conclude that GABA uptake inhibitors potentiate the actions of the GABAA receptor agonists, isoguvacine and muscimol, probably because they are effective substrates for GABA transporters in the ventral midbrain.

KW - γ-Aminobutyric acid (GABA) transporter

KW - Dopamine neuron

KW - Isoguvacine

KW - L-Arginine

KW - Muscimol

KW - NO 711

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U2 - 10.1016/S0014-2999(01)01218-3

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