Neuroactive steroids

Abstract

Neuroactive steroids are natural or synthetic steroids that rapidly alter the excitability of neurons by binding to membrane-bound receptors such as those for inhibitory and (or) excitatory neurotransmitters. The best-studied neuroactive steroids are a series of sedative-hypnotic 3 alpha-hydroxy ring A-reduced pregnane steroids that include the major metabolites of progesterone and deoxycorticosterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydroDOC), respectively. These 3 alpha-hydroxysteroids do not interact with classical intracellular steroid receptors but bind stereoselectively and with high affinity to receptors for the major inhibitory neurotransmitter in brain, gamma-amino-butyric acid (GABA). Biochemical and electrophysiological studies have shown that these steroids markedly augment GABA-activated chloride ion currents in a manner similar (but not identical) to that of anesthetic barbiturates. Several steroids have also been observed to have convulsant or proconvulsant properties, including the synthetic amidine 3 alpha-hydroxy-16-imino-5 beta-17-azaandrostan-11-one (RU5135) and the natural sulfate esters of pregnenolone and dehydroepiandrosterone. Several of these have been shown to be bicuculline or picrotoxin-like GABAA receptor antagonists. Examples of steroids that alter neuronal excitability rapidly by augmenting or inhibiting excitatory amino acid receptor-mediated responses have also been reported. Recently, allopregnanolone and allotetrahydroDOC have also been measured in brain and plasma where their levels have been shown to fluctuate in response to stress and during the estrous and menstrual cycles of rats and humans, respectively. Although the major fraction of allopregnanolone in tissue, including brain, is of adrenal and/or ovarian origin, appreciable levels of allopregnanolone can still be measured in the brains of adrenalectomized and/or oophorectomized animals. Receptor-active neurosteroids may represent an important class of neuromodulators that can rapidly alter central nervous system excitability via novel nongenomic mechanisms.

A Review of Glutamate Receptors I: Current Understanding of Their Biology

“…These neuroactive steroids bind with high affinity to GABA A receptors and have barbiturate-like actions in augmenting GABA-mediated responses 213 . The plasma and brain levels of these neuroactive steroids increase dramatically following exposure of rats to various stressors.…”

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

“…The 3α-reduced neuroactive steroids exhibit antidepressant and anxiolytic properties via interactions with the GABAergic system [59]. Neuroactive steroids are potent positive allosteric modulators of GABA A receptors as they increase the frequency or duration of opening of GABA-gated chloride channels [60,61]. In turn, GABA A chloride channels influence gene expression via intracellular progesterone receptors [62].…”

Stress, rejection, and hormones: Cortisol and progesterone reactivity to laboratory speech and rejection tasks in women and men

“…Progesterone is not only a gonadal hormone, but is also produced in the adrenal glands, and progesterone levels increase in response to pharmacological stimulation of the HPA axis ( Genazzani et al , 1998). Progesterone and hormones synthesized from it (e.g., allopregnanolone) increase during stress in laboratory animals ( Barbaccia et al , 2001; Paul & Purdy, 1992; Purdy et al , 1991), but it is as of yet unclear whether progesterone is part of the typical human stress response ( Wirth, 2011). There is evidence that progesterone does increase alongside cortisol during venipuncture stress ( Wirth, 2011), and also evidence that progesterone responds to the TSST stressor, at least in men, and in women in some menstrual cycle phases ( Childs et al , 2010).…”