Abstract
Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals, and the gonads and have potent and selective effects on the GABAA-receptor. 3α-hydroxy A-ring reduced metabolites of progesterone, deoxycorticosterone, and testosterone are positive modulators of GABAA-receptor in a non-genomic manner. Allopregnanolone (3α-OH-5α-pregnan-20-one), 5α-androstane-3α, 17α-diol (Adiol), and 3α5α-tetrahydrodeoxycorticosterone (3α5α-THDOC) enhance the GABA-mediated Cl- currents acting on a site (or sites) distinct from the GABA, benzodiazepine, barbiturate, and picrotoxin binding sites. 3α5α-P and 3α5α-THDOC potentiate synaptic GABAA-receptor function and activate δ-subunit containing extrasynaptic receptors that mediate tonic currents. On the contrary, 3β-OH pregnane steroids and pregnenolone sulfate (PS) are GABAA-receptor antagonists and induce activation-dependent inhibition of the receptor. The activities of neurosteroid are dependent on brain regions and types of neurons. In addition to the slow genomic action of the parent steroids, the non-genomic, and rapid actions of neurosteroids play a significant role in the GABAA-receptor function and shift in mood and memory function. This review describes molecular mechanisms underlying neurosteroid action on the GABAA-receptor, mood changes, and cognitive functions.
Highlights
Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals, and the gonads and have potent and selective effects on the GABAAreceptor. 3α-hydroxy A-ring reduced metabolites of progesterone, deoxycorticosterone, and testosterone are positive modulators of GABAA-receptor in a non-genomic manner
NEUROSTEROID Sex hormones act through genomic mechanisms through the intracellular receptors located in the nucleus or cytoplasm
The functional modulation of the GABAA-receptor by neurosteroids at low concentrations is believed to induce moderate to severe adverse mood changes in up to 20% of female individuals (Beauchamp et al, 2000; Fish et al, 2001)
Summary
Neurosteroids and GABAA-receptor function from cholesterol or steroidal precursors imported from peripheral sources (Schumacher et al, 2000; Baulieu et al, 2007) They include 3β-hydroxy-Δ5-compounds such as pregnenolone and dehydroepiandrosterone, their sulfate esters and reduced metabolites of steroid and stress hormones such as the tetrahydroderivative of progesterone, 3α-hydroxy-5α-pregnan-20-one (allopregnanolone; Baulieu et al, 2007). As metabolites of stress hormone deoxycorticosterone (DOC), 3α5α-THDOC and 3α5β-THDOC are potent modulators of the GABAA-receptor (Crawley et al, 1986; Majewska et al, 1986; Gasior et al, 1999; Lambert et al, 2001a) Both steroids have significant sedative effects in vivo.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
