Neuroactive steroids as modulators of depression and anxiety

Steroid hormone action in the brain involves binding to cognate intracellular receptors that in turn bind to respective response elements and thus modulate gene expression. We could demonstrate that 3α-reduced neuroactive steroids concurrently modulate the GABA_A receptor and regulate gene expression via the progesterone receptor using a cotransfection system in a human neuroblastoma cell line. An intracellular oxidation of GABAergic neuroactive steroids into 5α-pregnane steroids was identified as the molecular mechanism underlying the genomic effects of the neuroactive steroids because in contrast to the GABAergic neuroactive steroids the 5α-pregnane steroids are ligands for progesterone receptors. In vivo, progesterone and tetrahydroprogesterone produce a benzodiazepine-like sleep EEG profile in rats and humans. In addition, there is a dysequilibrium of 3α-reduced neuroactive steroids during major depression which is corrected by successful treatment with selective serotonin reuptake inhibitors but also with tri- and tetracyclic antidepressants. Studies in patients with panic disorder under basline conditions revealed changes in neuroactive steroid composition opposite to those in depression which may represent counterregulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimentally evoked panic attacks with either CCK-4 or sodium lactate there was a pronounced decline in the concentrations of 3α-reduced neuroactive steroids in patients with panic disorder that might result in a decreased GABAergic tone. In contrast, no changes in neuractive steroid concentrations could be observed in healthy controls irrespectively of the level of anxiety achieved with the exception of 3α, 5α-THDOC. This peripheral neuroactive steroid showed a pronounced increase after challenge with CCK-4 in healthy volunteers and may therefore contribute to the termination of anxiety and stress response during this challenge procedure. In conclusion, steroids exert both genomic and non-genomic effects in the brain that contribute to the pathophysiology of affective disorders and the mechanisms of action of antidepressants. Neuroactive steroids are important endogenous modulators of depression and anxiety and may provide a basis for novel therapeutic agents in the treatment of anxiety.