Potentiation, activation and blockade of GABAA receptors of clonal murine hypothalamic GT1-7 neurones by propofol

S Adodra, T G Hales

Research output: Contribution to journalArticle

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Abstract

1. The actions of GABA and the intravenous general anaesthetic propofol (2,6-diisopropylphenol) on GABAA receptors of self-replicating GT1-7 hypothalamic neurones were investigated by the patch clamp technique. 

2. GABA (1 microM-1 mM) dose-dependently activated inward currents with an EC50 of 27 microM, recorded from whole cells voltage-clamped at -60 mV. GABA (100 microM)-activated currents reversed at the Cl-equilibrium potential. 

3. Propofol (0.1-100 microM) dose-dependently potentiated GABA (100 microM)-evoked currents with an EC50 of 5 microM. 

4. In the absence of GABA, propofol (10 microM-1 mM) activated small inward currents with a reversal potential similar to the Cl- equilibrium potential. The peak current amplitudes activated by propofol were only 31% of those activated by GABA in the same cells. 

5. Like GABA (100 microM)-activated currents, propofol (100 microM)-activated currents were inhibited by the GABAA receptor antagonist, bicuculline (10 microM) and were abolished by Zn2+ (100 microM). 

6. Propofol (10, 30 and 100 microM) dose-dependently activated currents in the absence of GABA. However, the peak amplitude of currents activated by propofol declined with concentrations > 100 microM. The cessation of application of a high dose of propofol (1 mM) was associated with a current 'surge'. 

7. The surge current, seen after application of propofol (1 mM), had a reversal potential similar to the Cl- equilibrium potential. The ratio between peak current amplitude in the presence of propofol (1 mM) and surge current amplitude after propofol application, were not dependent on holding potential. Thus,it is unlikely that the surge current represents reversal of a voltage-dependent block of GABAA receptors by propofol.

8. The amplitude of the surge current exceeded the amplitude of the initial propofol (1 mM)-evoked current following brief applications, but declined after prolonged applications of the drug.

9. The observed modulatory actions of propofol may be due to separate potentiation, activation and inhibitory sites for this anaesthetic agent on GT1-7 cell GABAA receptors.

Original languageEnglish
Pages (from-to)953-60
Number of pages8
JournalBritish Journal of Pharmacology
Volume115
Issue number6
DOIs
Publication statusPublished - Jul 1995

Fingerprint

Propofol
GABA-A Receptors
Neurons
gamma-Aminobutyric Acid
Intravenous Anesthetics
GABA-A Receptor Antagonists
General Anesthetics
Bicuculline
Anesthetics

Keywords

  • Animals
  • Cells, Cultured/drug effects
  • Dose-Response Relationship, Drug
  • GABA-A Receptor Antagonists
  • Hypothalamus/drug effects
  • Membrane Potentials/drug effects
  • Mice
  • Patch-Clamp Techniques
  • Propofol/pharmacology
  • Receptors, GABA-A/drug effects
  • Time Factors
  • gamma-Aminobutyric Acid/pharmacology

Cite this

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title = "Potentiation, activation and blockade of GABAA receptors of clonal murine hypothalamic GT1-7 neurones by propofol",
abstract = "1. The actions of GABA and the intravenous general anaesthetic propofol (2,6-diisopropylphenol) on GABAA receptors of self-replicating GT1-7 hypothalamic neurones were investigated by the patch clamp technique. 2. GABA (1 microM-1 mM) dose-dependently activated inward currents with an EC50 of 27 microM, recorded from whole cells voltage-clamped at -60 mV. GABA (100 microM)-activated currents reversed at the Cl-equilibrium potential. 3. Propofol (0.1-100 microM) dose-dependently potentiated GABA (100 microM)-evoked currents with an EC50 of 5 microM. 4. In the absence of GABA, propofol (10 microM-1 mM) activated small inward currents with a reversal potential similar to the Cl- equilibrium potential. The peak current amplitudes activated by propofol were only 31{\%} of those activated by GABA in the same cells. 5. Like GABA (100 microM)-activated currents, propofol (100 microM)-activated currents were inhibited by the GABAA receptor antagonist, bicuculline (10 microM) and were abolished by Zn2+ (100 microM). 6. Propofol (10, 30 and 100 microM) dose-dependently activated currents in the absence of GABA. However, the peak amplitude of currents activated by propofol declined with concentrations > 100 microM. The cessation of application of a high dose of propofol (1 mM) was associated with a current 'surge'. 7. The surge current, seen after application of propofol (1 mM), had a reversal potential similar to the Cl- equilibrium potential. The ratio between peak current amplitude in the presence of propofol (1 mM) and surge current amplitude after propofol application, were not dependent on holding potential. Thus,it is unlikely that the surge current represents reversal of a voltage-dependent block of GABAA receptors by propofol.8. The amplitude of the surge current exceeded the amplitude of the initial propofol (1 mM)-evoked current following brief applications, but declined after prolonged applications of the drug.9. The observed modulatory actions of propofol may be due to separate potentiation, activation and inhibitory sites for this anaesthetic agent on GT1-7 cell GABAA receptors.",
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author = "S Adodra and Hales, {T G}",
year = "1995",
month = "7",
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Potentiation, activation and blockade of GABAA receptors of clonal murine hypothalamic GT1-7 neurones by propofol. / Adodra, S; Hales, T G.

In: British Journal of Pharmacology, Vol. 115, No. 6, 07.1995, p. 953-60.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Potentiation, activation and blockade of GABAA receptors of clonal murine hypothalamic GT1-7 neurones by propofol

AU - Adodra, S

AU - Hales, T G

PY - 1995/7

Y1 - 1995/7

N2 - 1. The actions of GABA and the intravenous general anaesthetic propofol (2,6-diisopropylphenol) on GABAA receptors of self-replicating GT1-7 hypothalamic neurones were investigated by the patch clamp technique. 2. GABA (1 microM-1 mM) dose-dependently activated inward currents with an EC50 of 27 microM, recorded from whole cells voltage-clamped at -60 mV. GABA (100 microM)-activated currents reversed at the Cl-equilibrium potential. 3. Propofol (0.1-100 microM) dose-dependently potentiated GABA (100 microM)-evoked currents with an EC50 of 5 microM. 4. In the absence of GABA, propofol (10 microM-1 mM) activated small inward currents with a reversal potential similar to the Cl- equilibrium potential. The peak current amplitudes activated by propofol were only 31% of those activated by GABA in the same cells. 5. Like GABA (100 microM)-activated currents, propofol (100 microM)-activated currents were inhibited by the GABAA receptor antagonist, bicuculline (10 microM) and were abolished by Zn2+ (100 microM). 6. Propofol (10, 30 and 100 microM) dose-dependently activated currents in the absence of GABA. However, the peak amplitude of currents activated by propofol declined with concentrations > 100 microM. The cessation of application of a high dose of propofol (1 mM) was associated with a current 'surge'. 7. The surge current, seen after application of propofol (1 mM), had a reversal potential similar to the Cl- equilibrium potential. The ratio between peak current amplitude in the presence of propofol (1 mM) and surge current amplitude after propofol application, were not dependent on holding potential. Thus,it is unlikely that the surge current represents reversal of a voltage-dependent block of GABAA receptors by propofol.8. The amplitude of the surge current exceeded the amplitude of the initial propofol (1 mM)-evoked current following brief applications, but declined after prolonged applications of the drug.9. The observed modulatory actions of propofol may be due to separate potentiation, activation and inhibitory sites for this anaesthetic agent on GT1-7 cell GABAA receptors.

AB - 1. The actions of GABA and the intravenous general anaesthetic propofol (2,6-diisopropylphenol) on GABAA receptors of self-replicating GT1-7 hypothalamic neurones were investigated by the patch clamp technique. 2. GABA (1 microM-1 mM) dose-dependently activated inward currents with an EC50 of 27 microM, recorded from whole cells voltage-clamped at -60 mV. GABA (100 microM)-activated currents reversed at the Cl-equilibrium potential. 3. Propofol (0.1-100 microM) dose-dependently potentiated GABA (100 microM)-evoked currents with an EC50 of 5 microM. 4. In the absence of GABA, propofol (10 microM-1 mM) activated small inward currents with a reversal potential similar to the Cl- equilibrium potential. The peak current amplitudes activated by propofol were only 31% of those activated by GABA in the same cells. 5. Like GABA (100 microM)-activated currents, propofol (100 microM)-activated currents were inhibited by the GABAA receptor antagonist, bicuculline (10 microM) and were abolished by Zn2+ (100 microM). 6. Propofol (10, 30 and 100 microM) dose-dependently activated currents in the absence of GABA. However, the peak amplitude of currents activated by propofol declined with concentrations > 100 microM. The cessation of application of a high dose of propofol (1 mM) was associated with a current 'surge'. 7. The surge current, seen after application of propofol (1 mM), had a reversal potential similar to the Cl- equilibrium potential. The ratio between peak current amplitude in the presence of propofol (1 mM) and surge current amplitude after propofol application, were not dependent on holding potential. Thus,it is unlikely that the surge current represents reversal of a voltage-dependent block of GABAA receptors by propofol.8. The amplitude of the surge current exceeded the amplitude of the initial propofol (1 mM)-evoked current following brief applications, but declined after prolonged applications of the drug.9. The observed modulatory actions of propofol may be due to separate potentiation, activation and inhibitory sites for this anaesthetic agent on GT1-7 cell GABAA receptors.

KW - Animals

KW - Cells, Cultured/drug effects

KW - Dose-Response Relationship, Drug

KW - GABA-A Receptor Antagonists

KW - Hypothalamus/drug effects

KW - Membrane Potentials/drug effects

KW - Mice

KW - Patch-Clamp Techniques

KW - Propofol/pharmacology

KW - Receptors, GABA-A/drug effects

KW - Time Factors

KW - gamma-Aminobutyric Acid/pharmacology

U2 - 10.1111/j.1476-5381.1995.tb15903.x

DO - 10.1111/j.1476-5381.1995.tb15903.x

M3 - Article

C2 - 7582526

VL - 115

SP - 953

EP - 960

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 6

ER -