A theory of the anxiolytic action of flumazenil in anxiety disorders

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 GABAA receptor, is synthesised in response to stress and acts to negatively modulate the hypothalamic-pituitary-adrenal axis.After chronic exposure to and withdrawal from allopregnanolone, an increase in α4β2δ GABAA 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 GABAA 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 GABAA receptor antagonist, has been shown to cause receptor internalisation of α4β2δ GABAA receptors, which may results in anxiolysis.We propose that chronic stress and chronic exposure to and withdrawal from allopregnanolone in anxiety disorders result in alterations in GABAA receptor function, which can be corrected by flumazenil. As such, flumazenil may exhibit anxiolytic properties in patients with increased α4β2δ GABAA receptor expression.