An interaction between benzodiazepines and neuroactive steroids at GABAA receptors in cultured hippocampal neurons
Document Type
Article
Publication Title
Neurochemistry International
ISSN
0197-0186
Volume
48
Issue
8
DOI
10.1016/j.neuint.2005.12.006
First Page
703
Last Page
707
Publication Date
6-1-2006
Abstract
Neurosteroids are modulators of several receptors and ion channels and are implicated in the pathophysiology of several neuropsychiatric diseases including hepatic encephalopathy (HE). The neurosteroid, allopregnanolone, a positive allosteric modulator of GABA receptors, accumulates in the brains of HE patients where it can potentiate GABA receptor-mediated responses. Attenuation of the effects of neurosteroids on GABA-ergic neurotransmission is therefore of interest for the management of HE. In the present study, we determined the effect of the benzodiazepine partial inverse agonist, Ro15-4513, and the benzodiazepine antagonist, flumazenil on modulation of the GABA mediated chloride currents by allopregnanolone and on spontaneous synaptic activity in cultured hippocampal neurons using the patch-clamp technique. Allopregnanolone (0.03-0.3 μM), dose-dependently potentiated GABA-induced currents, an action significantly reduced by Ro15-4513 (10 μM). In contrast, flumazenil (10 μM) had no effect on the ability of allopregnanolone to potentiate GABA currents but it blocked the effects of Ro15-4513. The frequency of spontaneous synaptic activity was significantly reduced in the presence of allopregnanolone (0.1 μM) from 1.5 ± 0.7 to 0.1 ± 0.04 Hz. This action was partially reversed by Ro15-4513 (10 μM) but was not significantly influenced by flumazenil (10 μM). These findings suggest that the beneficial affects of Ro15-4513 in experimental HE result from attenuation of the effects of neurosteroids at GABA receptors. Our results may provide a rational basis for the use of benzodiazepine inverse agonists in the management and treatment of hepatic encephalopathy in patients with liver failure. © 2006 Elsevier Ltd. All rights reserved. A A A A A
Recommended Citation
Ahboucha, S.,
Coyne, L.,
Hirakawa, R.,
Butterworth, R. F.,
&
Halliwell, R. F.
(2006).
An interaction between benzodiazepines and neuroactive steroids at GABAA receptors in cultured hippocampal neurons.
Neurochemistry International, 48(8), 703–707.
DOI: 10.1016/j.neuint.2005.12.006
https://scholarlycommons.pacific.edu/phs-facarticles/414
