Neurosteroid modulation of GABAA receptors

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

“…Positive neurosteroid modulators elicit potentiation of both γ 1 -and γ 2 -containing GABA A receptors, although variable effects of γ subunit composition on efficacy and potency have been reported (Puia et al, 1993;for review, Belelli et al, 2002;Lambert et al, 2003). The ε subunit shares the greatest sequence homology with the γ subunits, and so it is generally thought to take the place of the single γ subunit in the pentameric receptor.…”

“…Using this methodology, allopregnanolone concentrations in cortical homogenates were estimated to be ~1-2 ng/g in juvenile, ~1 ng/g in diestrous, 4-6 ng/g in estrous, and 4-8 ng/g in proestrous females, with levels reaching ~10-30 ng/g during pregnancy (Paul and Purdy, 1992;Corpéchot et al, 1993;Concas et al, 1998;Kellogg and Frye, 1999). These assessments have been used to estimate that allopregnanolone levels are diestrus females (Paul and Purdy, 1992), but can reach ~100 nM during the late stages of pregnancy (see for example; Brussaard et al, 1997;Lambert et al, 2003). The androgenic neurosteroid, 3α-diol, also showed cycle-dependent variation in cortical homogenates, with levels being lowest in diestrus I (0.08 ng/g) and rising steadily as the cycle progresses to a maximum of 0.33 ng/g during estrus (Kellogg and Frye, 1999).…”

“…This remains a somewhat open question, especially in juvenile or diestrus females and adult males, since the estimates obtained with RIAs may be artefactually high and EC 50 values, for example, for allopregnanolone potentiation of different isoforms of recombinant GABA A receptors activated by an EC 10 concentration of GABA, range from ~75 to 560 nM (Lambert et al, 2003). While these data might suggest minimal potentiation by allopregnanolone and other neurosteroids except during very restricted hormonal states, such as pregnancy, such generalization need to be made with caution since estimates made for large brain regions, even by improved chromatography/spectrometry techniques, do not reflect neurosteroid concentrations in microdomains, such as synapses, where synthesis in nearby glial cells and restricted diffusion/clearance may produce greatly elevated concentrations in the local environments of the GABA A receptors.…”

“…Although neurosteroid modulation of GABA A receptor-mediated responses was first noted in the early 1980s (for review, Lambert et al, 2003), steroid modulation of neurons in neuroendocrine control regions has been assessed only during the past decade. Initial studies concentrated on modulation of GABA A receptor-mediated responses in dissociated embryonic hypothalamic neurons, while more recent reports have examined effects of steroid modulators in defined regions/nuclei of acutely isolated slices.…”

Acute 19-nortestosterone transiently suppresses hippocampal MAPK pathway and the phosphorylation of the NMDA receptor

“…The function of ion channels such as NMDA and GABA receptors can be rapidly modulated by neurosteroids through allosteric interactions at receptor sites [48]. AAS and neurosteroids show structural similarity, yet they can distinctively modulate the GABA A receptor due to differences at critical moieties [49]. With respect to the NMDAR we have previously shown that the neurosteroids, e.g.…”