An interaction between benzodiazepines and neuroactive steroids at GABA A receptors in cultured hippocampal neurons.

  • Ahboucha S
  • Coyne L
  • Hirakawa R
 et al. 
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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(A) receptors, accumulates in the brains of HE patients where it can potentiate GABA(A) 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(A) mediated chloride currents by allopregnanolone and on spontaneous synaptic activity in cultured hippocampal neurons using the patch-clamp technique. Allopregnanolone (0.03-0.3 microM), dose-dependently potentiated GABA-induced currents, an action significantly reduced by Ro15-4513 (10 microM). In contrast, flumazenil (10 microM) had no effect on the ability of allopregnanolone to potentiate GABA(A) 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 microM) from 1.5+/-0.7 to 0.1+/-0.04Hz. This action was partially reversed by Ro15-4513 (10 microM) but was not significantly influenced by flumazenil (10 microM). These findings suggest that the beneficial affects of Ro15-4513 in experimental HE result from attenuation of the effects of neurosteroids at GABA(A) 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.

Author-supplied keywords

  • Affinity Labels
  • Affinity Labels: pharmacology
  • Allosteric Regulation
  • Allosteric Regulation: drug effects
  • Allosteric Regulation: physiology
  • Animals
  • Azides
  • Azides: pharmacology
  • Benzodiazepines
  • Benzodiazepines: pharmacology
  • Cells, Cultured
  • Chloride Channels
  • Chloride Channels: drug effects
  • Chloride Channels: metabolism
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Interactions: physiology
  • Female
  • Flumazenil
  • Flumazenil: pharmacology
  • GABA Modulators
  • GABA Modulators: pharmacology
  • Hepatic Encephalopathy
  • Hepatic Encephalopathy: drug therapy
  • Hepatic Encephalopathy: metabolism
  • Hepatic Encephalopathy: physiopathology
  • Hippocampus
  • Hippocampus: cytology
  • Hippocampus: drug effects
  • Hippocampus: metabolism
  • Male
  • Neural Inhibition
  • Neural Inhibition: drug effects
  • Neural Inhibition: physiology
  • Neurons
  • Neurons: drug effects
  • Neurons: metabolism
  • Patch-Clamp Techniques
  • Pregnanolone
  • Pregnanolone: metabolism
  • Pregnanolone: pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A
  • Receptors, GABA-A: drug effects
  • Receptors, GABA-A: metabolism
  • Synaptic Transmission
  • Synaptic Transmission: drug effects
  • Synaptic Transmission: physiology

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Authors

  • Samir Ahboucha

  • Leanne Coyne

  • Ryoko Hirakawa

  • Roger F Butterworth

  • Robert F Halliwell

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