Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor.
The neurosteroid allopregnanolone (ALLO) or 3alpha-OH-5alpha-pregnane-20-one interacts with the GABA type A receptor chloride ion channel complex and enhances the effect of GABA. Animal and human studies suggest that ALLO plays an important role in several disorders including premenstrual syndrome, anxiety, and memory impairment. In contrast to ALLO, steroids with a hydroxy group in the 3beta position usually exert a reducing effect and have recently attracted interest due to their suggested role in counteracting the negative action of ALLO. In this study, five different 3beta-steroids were tested for their ability to modulate GABA-mediated chloride ion uptake in the absence and presence of ALLO in rat brain microsacs preparations. In addition, the effects of the 3beta-steroids and their interaction with ALLO were investigated by patch-clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) in rat hypothalamic neurons from the medial preoptic nucleus (MPN). All tested 3beta-steroids reduced the ALLO-enhanced GABA response in cerebral cortex, in hippocampus and in MPN. In cerebellum, only one had this effect. However, in the absence of ALLO, two of the 3beta-steroids potentiated GABA-evoked chloride ion uptake and prolonged the sIPSCs decay time, whereas the others had little or no effect. Therefore, it is possible that at least some 3beta-steroids can act as positive GABA(A) receptor modulators as well as negative modulators depending on whether or not ALLO is present. Finally, these results suggest that the 3beta-steroids could be of interest as pharmacological agents that could counteract the negative effects of ALLO.
Strömberg
J
J
Umeå Neurosteroid Research Center, Obstetrics and Gynecology, Department of Clinical Science, Umeå University, Norrland University Hospital, Building 5B level 5, SE 901 85 Umeå, Sweden. Jessica.Stromberg@obgyn.umu.se
Haage
D
D
Taube
M
M
Bäckström
T
T
Lundgren
P
P
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D011280:Pregnanolone / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D013256:Steroids / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D018118:Chloride Channels; D002712:Chlorides; D011963:Receptors, GABA-A; D013256:Steroids; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone