γ-Aminobutyric acid, acting through γ-aminobutyric acid type A receptors, inhibits the biosynthesis of neurosteroids in the frog hypothalamus

Abstract

Most of the actions of neurosteroids on the central nervous system are mediated through allosteric modulation of the ␥-aminobutyric acid type A (GABA A) receptor, but a direct effect of GABA on the regulation of neurosteroid biosynthesis has never been investigated. In the present report, we have attempted to determine whether 3␤-hydroxysteroid dehydrogenase (3␤-HSD)-containing neurons, which secrete neurosteroids in the frog hypothalamus, also express the GABAA receptor, and we have investigated the effect of GABA on neurosteroid biosynthesis by frog hypothalamic explants. Double immunohistochemical labeling revealed that most 3␤-HSD-positive neurons also contain GABAA receptor ␣3 and ␤2͞␤3 subunit-like immunoreactivities. Pulse-chase experiments showed that GABA inhibited in a dose-dependent manner the conversion of tritiated pregnenolone into radioactive steroids, including 17-hydroxy-pregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, and dihydrotestosterone. The effect of GABA on neurosteroid biosynthesis was mimicked by the GABA A receptor agonist muscimol but was not affected by the GABA B receptor agonist baclofen. The selective GABAA receptor antagonists bicuculline and SR95531 reversed the inhibitory effect of GABA on neurosteroid formation. The present results indicate that steroid-producing neurons of the frog hypothalamus express the GABAA receptor ␣3 and ␤2͞␤3 subunits. Our data also demonstrate that GABA, acting on GABA A receptors at the hypothalamic level, inhibits the activity of several key steroidogenic enzymes, including 3␤-HSD and cytochrome P450C17 (17␣-hydroxylase).neuroactive steroids ͉ 3␤-hydroxysteroid dehydrogenase ͉ GABA A-benzodiazepine receptor complex

GABAergic dysfunction in mood disorders

“…However, no significant differences between suicide victims and nonpsychiatric controls for GABA A and GABA B receptor binding sites, [142][143][144][145] GAD activity, 141 and GABA concentration 146 have been found in several brain areas. Recently, support for abnormally decreased GABAergic neurotransmission in anterior cingulate, prefrontal cortex, and hippocampus in bipolar, but not unipolar disorder patients has been reported by several postmortem studies, as shown by decreased expression of GAD 65 and GAD 67 and decreased density of GABAergic neurons. [147][148][149][150] These post-mortem studies together sustain the hypothesis of low GABA brain activity in mood disorder patients, but not in suicide victims.…”

“…In turn, pregnenolone can be metabolized to pregnanes (pregnenolone sulfate, pregnanolone, allopregnanolone) and androstanes (dehydroepiandrosterone, dehydroepiandrosterone-sulfate, dihydrotestoterone metabolites). 66 Although the mechanisms involved in the regulation of neurosteroids within the cells are still largely unknown, Do-Rego et al 67 have recently reported that GABA itself, acting through GABA A receptors, inhibits the activity of neurosteroidogenic enzymes. The effects of neurosteroids on GABA A receptors have been extensively investigated.…”

Neuroactive Steroids and Affective Symptoms in Women Across the Weight Spectrum

“…This could be consistent with the work from Girdler et al (2012) showing decreased conversion of progesterone to allopregnanolone in women with a history of depression. Research in a frog model also shows that GABA A receptor activation can lead to a downregulation of neuroactive steroid production, suggesting a potential negative feedback loop; however, this has not been investigated in humans (Do-Rego et al, 2000). Thus, while neurosteroidogenic pathways are well defined, the overall regulation of neuroactive steroids is not yet fully understood.…”

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

“…Moreover, these different variables are also likely to be dependent upon one another. Finally, it is noted that activation of hypothalamic GABA A receptors has been shown to inhibit the activity of the steroidogenic enzymes, 3β-hydroxysteroid dehydrogenase and P450 C17 (17α-hydroxylase) and neurosteroid production in the hypothalamus, suggesting that neurosteroid potentiation of hypothalamic GABAergic transmission may be self-limiting (Do-Rego et al, 2000). A) Representative micrograph of an acutely isolated slice from a female mouse at the level of the mPOA and a patch electrode.…”