Neuroactive steroids as endogenous modulators of anxiety

In the past decades considerable evidence has emerged that certain so called neuroactive steroids not only act as transcription factors in the regulation of gene expression but may also alter neuronal excitability through interaction with specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABA(A)), N-methyl-D-aspartate (NMDA) and glutamate receptors. There is growing evidence that neuroactive steroids play an important role as endogenous modulators of neuronal function and behavioural processes and that alterations of endogenous neuroactive steroid concentrations may contribute to the pathophysiology of affective disorders. In view of their positive allosteric potential at GABA(A)-receptors, especially 3alpha-reduced neuroactive steroids have been suggested to play a major role in the pathophysiology of anxiety disorders. In panic disorder patients a dysequilibrium of neuroactive steroid composition has been observed, which may represent counterregulatory mechanisms against the occurrence of spontaneous panic attacks. Therefore, attenuation of neuroactive steroid concentrations either by synthetic derivates of neuroactive steroids or by modulation of endogenous neurosteroid synthesis might constitute a promising novel strategy for the treatment of anxiety disorders. In conclusion, neuroactive steroids are important endogenous modulators of depression and anxiety and may provide a basis for development of novel therapeutic agents in the treatment of affective disorders.