Possible Interaction: Gamma-Aminobutyric Acid and Pregnanolone

“Pregnanolone isomers PIs ) and their polar conjugates (PICs) modulate ionotropic receptors such as gamma-aminobutyric acid or pregnane X receptors.”

“Our results indicate that the pregnanolone derivatives , in contrast to the androstane analogues, modulate IGABA and IGly at low micromolar concentrations and this family of neurosteroids can be useful for future structure‐activity relationship studies of the steroid modulation of other receptor types.”

“Fluctuations in the concentrations of the neuroactive steroid allopregnanolone are thought to influence γ-amino-butyric acid type A (GABA(A)) receptor gene expression and function.”

“Allopregnanolone (1) and pregnanolone (2), steroids containing a 17beta-acetyl group, are potent enhancers of GABA (gamma-aminobutyric acid) action at GABAA receptors.”

“These GABA concentrations activated low-conducting channels (<40 pS) in 78% … conductance above 40 pS. Alphaxalone at concentrations above 1 microM, and pregnanolone at concentrations above 0.… channels activated by GABA up to seven-fold and at all concentrations tested, … decreased closed probability and mean closed time of channels.”

“For example, the pregnane neurosteroid allopregnanolone (ALLOP) is a potent positive modulator of gamma-aminobutyric acid(A) (GABA(A)) receptors.”

“These results suggest that positive GABAA modulation is one mechanism by which pregnanolone decreases FR responding, and that dependence resulting from daily pregnanolone treatment is not necessarily accompanied by tolerance to pregnanolone.”

“The progesterone metabolites allopregnanolone (Allo, 3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (Preg, 3alpha-hydroxy-5beta-pregnan-20-one) enhance the gamma-aminobutyric acid (GABA) action through a distinct site on the GABAA-receptor.”

“Bath perfusion of 3alpha-isomers of pregnanolone or tetrahydrodeoxycorticosterone (1 microM) significantly enhanced the current evoked by short pulses of GABA (3 microM) and accelerated its desensitization.”

“ PGN shifted the concentration-response relationship for GABA to the left with a suppression of the maximal response to GABA, resulting from the rapid inactivation of the GABA response during PGN treatment.”