A theory of the anxiolytic action of flumazenil in anxiety disorders

Background: Anxiety disorders are highly prevalent affecting up to 33.7% of people over a lifetime. Although many treatment options are available, they are often associated with unacceptable side-effect profiles and approximately one in three patients are treatment resistant. Allopregnanolone, a neuroactive steroid acting as a positive allosteric modulator at the GABA_A receptor, is synthesised in response to stress and acts to negatively modulate the hypothalamic–pituitary–adrenal axis. Findings: After chronic exposure to and withdrawal from allopregnanolone, an increase in α₄β₂δ GABA_A receptors results in a reduced inhibitory effect of allopregnanolone, resulting in decreased inhibition and, therefore, increased neuronal excitability. The relationship between allopregnanolone and increased α₄β₂δ GABA_A receptors has been demonstrated in animal models during methamphetamine withdrawal and puberty, events both associated with stress. The effect of allopregnanolone during these events is anxiogenic, a paradoxical action to its usual anxiolytic effects. Flumazenil, the GABA_A receptor antagonist, has been shown to cause receptor internalisation of α₄β₂δ GABA_A receptors, which may results in anxiolysis. Conclusion: We propose that chronic stress and chronic exposure to and withdrawal from allopregnanolone in anxiety disorders result in alterations in GABA_A receptor function, which can be corrected by flumazenil. As such, flumazenil may exhibit anxiolytic properties in patients with increased α₄β₂δ GABA_A receptor expression.