GABAergic effects of neuroactive steroids: Modulation of sleep and anxiety

3α-reduced neuroactive steroids such as 3α, 5α-tetrahydroprogesterone are potent positve allosteric modulators of GABA_A receptors. We conducted several studies in rats and humans using spectral analysis of sleep. Acute progesterone administration reduced slow wave sleep and increased spindle frequencies in rats or humans. This sleep EEG profile was quite similar to that obtained with benzodiazepines. In view of the pronounced anxiolytic activity of 3α-reduced neuroactive steroids in animal models we investigated their putative role in patients with panic disorder. During panic attacks which were experimentally induced either by CCK-4 or sodium lactate there was a pronounced drop of GABAagonistic 3α-reduced neuroactive steroids which was accompanied by an increase in a 3ß-reduced isomer in patients with panic disorder but not in healthy controls. This composition of neuroactive steroids may result in a decrease GABAergic tone which might contribute to the pathophysiology of panic attacks in patients with panic disorder. Thus, GABAergic neuroactive steroids appear to be potent endogenous modulators of sleep and anxiety and may also constitute novel treatment strategies.