Neuroactive steroid regulation of neurotransmitter release in the CNS: Action, mechanism and possible significance

Neuroactive steroids refer to steroids that are capable of regulating neuronal activities. Neuroactive steroids, synthesized either de novo in the nervous tissue or in the peripheral endocrine glands or as synthetic steroids, have exhibited numerous important modulatory effects on brain functions and brain diseases. At the cellular level, in addition to the effect on postsynaptic receptors, most neuroactive steroids, including pregnenolone, pregnenolone sulfate, progesterone, allopregnanolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone and estradiol, have modulatory effects on the release of multiple neurotransmitters like glutamate, GABA, acetylcholine, norepinephrine, dopamine and 5-HT. Many of these effects occur in the brain regions involved in learning and memory, emotion, motivation, motor and cognition. Moreover, the effects are rather complicated, maybe depending on many factors such as types of neuroactive steroids, brain regions and presynaptic functional states. The mechanisms are also complicated. Many of them involve rapid non-genomic effects on presynaptic receptors and ion channels like sigma-1 receptor, α1 receptor, nicotine receptor, D1 receptor, NMDA receptor, GABAA receptor and L-type Ca2+ channels. These effects have made neuroactive steroids important regulators of synaptic transmission in the central nervous system and constitute the major basis for many important actions of neuroactive steroids on brain functions and brain diseases.