Modulation of GABAA receptor activity by alphaxalone

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Abstract

The modulation of the γ‐aminobutyric acidA (GABAA) receptor by alphaxalone has been investigated by use of voltage‐clamp recordings from enzymatically isolated bovine chromaffin cells maintained in cell culture. Alphaxalone (> 30 nm) reversibly and dose‐dependently potentiated the amplitude of membrane currents elicited by locally applied GABA (100 μm). The potentiation was not associated with a change in the reversal potential of GABA‐evoked currents and was not influenced by the benzodiazepine receptor antagonist, Ro15‐1788 (300 nm). At relatively high concentrations (> 1 μm), alphaxalone directly elicited a membrane current. It is concluded that such currents result from GABAA receptor activation since they were reversibly suppressed by bicuculline (3 μm), dose‐dependently enhanced by phenobarbitone (100–500 μm), and had a similar reversal potential (∼ 0 mV) to currents elicited by GABA. Additionally, on outside‐out membrane patches, alphaxalone activated single channel currents with amplitudes and a reversal potential similar to those evoked by GABA. Alphaxalone (30 nm‐1 μm) had no effect upon the amplitude of membrane currents elicited by locally applied acetylcholine (ACh) (100 μm). However, higher concentrations of alphaxalone (10–100 μm) reversibly suppressed ACh‐evoked currents, the IC50 for blockade being 20 μm. The β‐hydroxy isomer of alphaxalone, betaxalone (100 nm‐1 μm), did not potentiate GABA‐induced currents, nor did higher concentrations of the steroid (10–100 μm) directly evoke a membrane current. However, over the latter concentration range, betaxalone suppressed the amplitude of currents elicited either by GABA or ACh. The relevance of the present results to the anaesthetic action of alphaxalone is discussed together with the broader implications of steroidal modulation of the GABAA receptor. 1987 British Pharmacological Society

Original languageEnglish
Pages (from-to)491-500
Number of pages10
JournalBritish Journal of Pharmacology
Volume90
Issue number3
DOIs
Publication statusPublished - Mar 1987

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GABA-A Receptors
gamma-Aminobutyric Acid
Membranes
Acetylcholine
Chromaffin Cells
Bicuculline
alphaxalone
Phenobarbital
Inhibitory Concentration 50
Anesthetics
Cell Culture Techniques
Steroids

Cite this

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title = "Modulation of GABAA receptor activity by alphaxalone",
abstract = "The modulation of the γ‐aminobutyric acidA (GABAA) receptor by alphaxalone has been investigated by use of voltage‐clamp recordings from enzymatically isolated bovine chromaffin cells maintained in cell culture. Alphaxalone (> 30 nm) reversibly and dose‐dependently potentiated the amplitude of membrane currents elicited by locally applied GABA (100 μm). The potentiation was not associated with a change in the reversal potential of GABA‐evoked currents and was not influenced by the benzodiazepine receptor antagonist, Ro15‐1788 (300 nm). At relatively high concentrations (> 1 μm), alphaxalone directly elicited a membrane current. It is concluded that such currents result from GABAA receptor activation since they were reversibly suppressed by bicuculline (3 μm), dose‐dependently enhanced by phenobarbitone (100–500 μm), and had a similar reversal potential (∼ 0 mV) to currents elicited by GABA. Additionally, on outside‐out membrane patches, alphaxalone activated single channel currents with amplitudes and a reversal potential similar to those evoked by GABA. Alphaxalone (30 nm‐1 μm) had no effect upon the amplitude of membrane currents elicited by locally applied acetylcholine (ACh) (100 μm). However, higher concentrations of alphaxalone (10–100 μm) reversibly suppressed ACh‐evoked currents, the IC50 for blockade being 20 μm. The β‐hydroxy isomer of alphaxalone, betaxalone (100 nm‐1 μm), did not potentiate GABA‐induced currents, nor did higher concentrations of the steroid (10–100 μm) directly evoke a membrane current. However, over the latter concentration range, betaxalone suppressed the amplitude of currents elicited either by GABA or ACh. The relevance of the present results to the anaesthetic action of alphaxalone is discussed together with the broader implications of steroidal modulation of the GABAA receptor. 1987 British Pharmacological Society",
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Modulation of GABAA receptor activity by alphaxalone. / Cottrell, Glen A.; Lambert, Jeremy J.; Peters, John A.

In: British Journal of Pharmacology, Vol. 90, No. 3, 03.1987, p. 491-500.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Modulation of GABAA receptor activity by alphaxalone

AU - Cottrell, Glen A.

AU - Lambert, Jeremy J.

AU - Peters, John A.

PY - 1987/3

Y1 - 1987/3

N2 - The modulation of the γ‐aminobutyric acidA (GABAA) receptor by alphaxalone has been investigated by use of voltage‐clamp recordings from enzymatically isolated bovine chromaffin cells maintained in cell culture. Alphaxalone (> 30 nm) reversibly and dose‐dependently potentiated the amplitude of membrane currents elicited by locally applied GABA (100 μm). The potentiation was not associated with a change in the reversal potential of GABA‐evoked currents and was not influenced by the benzodiazepine receptor antagonist, Ro15‐1788 (300 nm). At relatively high concentrations (> 1 μm), alphaxalone directly elicited a membrane current. It is concluded that such currents result from GABAA receptor activation since they were reversibly suppressed by bicuculline (3 μm), dose‐dependently enhanced by phenobarbitone (100–500 μm), and had a similar reversal potential (∼ 0 mV) to currents elicited by GABA. Additionally, on outside‐out membrane patches, alphaxalone activated single channel currents with amplitudes and a reversal potential similar to those evoked by GABA. Alphaxalone (30 nm‐1 μm) had no effect upon the amplitude of membrane currents elicited by locally applied acetylcholine (ACh) (100 μm). However, higher concentrations of alphaxalone (10–100 μm) reversibly suppressed ACh‐evoked currents, the IC50 for blockade being 20 μm. The β‐hydroxy isomer of alphaxalone, betaxalone (100 nm‐1 μm), did not potentiate GABA‐induced currents, nor did higher concentrations of the steroid (10–100 μm) directly evoke a membrane current. However, over the latter concentration range, betaxalone suppressed the amplitude of currents elicited either by GABA or ACh. The relevance of the present results to the anaesthetic action of alphaxalone is discussed together with the broader implications of steroidal modulation of the GABAA receptor. 1987 British Pharmacological Society

AB - The modulation of the γ‐aminobutyric acidA (GABAA) receptor by alphaxalone has been investigated by use of voltage‐clamp recordings from enzymatically isolated bovine chromaffin cells maintained in cell culture. Alphaxalone (> 30 nm) reversibly and dose‐dependently potentiated the amplitude of membrane currents elicited by locally applied GABA (100 μm). The potentiation was not associated with a change in the reversal potential of GABA‐evoked currents and was not influenced by the benzodiazepine receptor antagonist, Ro15‐1788 (300 nm). At relatively high concentrations (> 1 μm), alphaxalone directly elicited a membrane current. It is concluded that such currents result from GABAA receptor activation since they were reversibly suppressed by bicuculline (3 μm), dose‐dependently enhanced by phenobarbitone (100–500 μm), and had a similar reversal potential (∼ 0 mV) to currents elicited by GABA. Additionally, on outside‐out membrane patches, alphaxalone activated single channel currents with amplitudes and a reversal potential similar to those evoked by GABA. Alphaxalone (30 nm‐1 μm) had no effect upon the amplitude of membrane currents elicited by locally applied acetylcholine (ACh) (100 μm). However, higher concentrations of alphaxalone (10–100 μm) reversibly suppressed ACh‐evoked currents, the IC50 for blockade being 20 μm. The β‐hydroxy isomer of alphaxalone, betaxalone (100 nm‐1 μm), did not potentiate GABA‐induced currents, nor did higher concentrations of the steroid (10–100 μm) directly evoke a membrane current. However, over the latter concentration range, betaxalone suppressed the amplitude of currents elicited either by GABA or ACh. The relevance of the present results to the anaesthetic action of alphaxalone is discussed together with the broader implications of steroidal modulation of the GABAA receptor. 1987 British Pharmacological Society

U2 - 10.1111/j.1476-5381.1987.tb11198.x

DO - 10.1111/j.1476-5381.1987.tb11198.x

M3 - Article

C2 - 3032320

AN - SCOPUS:0023160992

VL - 90

SP - 491

EP - 500

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 3

ER -