Neuroactive steroids: their mechanism of action and their function in the stress response

Steroids are usually identified as genomic regulators, yet recently a body of evidence has accumulated demonstrating specific plasma membrane effects, as well as coordinative effects, of some steroids on both membrane and int racellular receptors. The resulting rapid (< 1 min) modulation of cellular activity has strongly suggested a non-genomic, and possibly modulatory, rol e for certain steroid compounds, and dramatic effects on membranes of excit able as well as other tissues have been demonstrated. Steroid synthesis and metabolism have been shown to exist in the CNS, and the effects have been seen in both the central and peripheral nervous systems. The major groups o f neuroactive steroids, and their metabolites, have been progesterone, deox ycorticosterone, and some androgens, notably dihydroxyepiandrosterone (DHEA ). These compounds show increased concentrations both in blood and in the b rain following stress and they have also been associated with anxiolytic ef fects and antiepileptic activity. In the periphery, some of these compounds show remarkable inhibitory effects on the secretion of catecholamines and other neurotransmitters. The mechanism for the majority of the effects of t hese steroids is via their effect on receptor-mediated binding to ligand-ga ted ion channels. Activation of the GABA(A) receptor complex, resulting in the opening of its central chloride channel, is the major target of the neu roactive steroids, resulting in re-polarization of the plasma membrane and inhibition of further neuronal firing. The anxiolytic, anti-convulsant and sedative-hypnotic actions of these neuroactive steroids have resulted in th eir being used as therapeutic agents for the treatment of anxiety, epilepsy , insomnia, and possibly for the alteration of pain thresholds.