Stress responses are activated by the hypothalamic-pituitary-adrenal axis (HPA axis), culminating in the release of glucocorticoids. During prolonged periods of secretion of glucocorticoids or inappropriate behavioral responses to a stressor, pathologic conditions may occur. Increased glucocorticoid concentration is linked to generalized anxiety, and there are knowledge gaps regarding its regulation. It is known that the HPA axis is under GABAergic control, but the contribution of the individual subunits of the GABA receptor is largely unknown. In this study, we investigated the relationship between the α5 subunit and corticosterone levels in a new mouse model deficient for Gabra5, which is known to be linked to anxiety disorders in humans and phenologs observed in mice. We observed decreased rearing behavior, suggesting lower anxiety in the Gabra5-/- animals; however, such a phenotype was absent in the open field and elevated plus maze tests. In addition to decreased rearing behavior, we also found decreased levels of fecal corticosterone metabolites in Gabra5-/- mice indicating a lowered stress response. Moreover, based on the electrophysiological recordings where we observed a hyperpolarized state of hippocampal neurons, we hypothesize that the constitutive ablation of the Gabra5 gene leads to functional compensation with other channels or GABA receptor subunits in this model.

• Keywords
• GABA receptor, anxiety, behavior, corticosterone, mouse model,
• MeSH
• Glucocorticoids * MeSH
• Corticosterone * MeSH
• Humans MeSH
• Mice MeSH
• Receptors, GABA-A genetics   metabolism   MeSH
• Receptors, GABA metabolism   MeSH
• Pituitary-Adrenal System metabolism   MeSH
• Hypothalamo-Hypophyseal System metabolism   MeSH
• Anxiety MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• GABRA5 protein, human MeSH Browser
• Gabra5 protein, mouse MeSH Browser
• Glucocorticoids * MeSH
• Corticosterone * MeSH
• Receptors, GABA-A MeSH
• Receptors, GABA MeSH

BACKGROUND: Pregnanolone isomers (PI) with a hydroxy group in the 3alpha-position are neuroinhibitors operating via positive modulation of GABA(A) receptors. The 3beta-PI and sulfates of PI and pregnenolone exert the opposite effect. In addition to the brain's in situ synthesis, some circulating steroids can penetrate the blood-brain barrier. METHODS: To assess the physiological impact of peripheral endogenous neuroactive pregnanolone isomers and their polar conjugates in women, serum allopregnanolone (P3alpha5alpha), isopregnanolone (P3beta5alpha), pregnanolone (P3alpha5beta), epipregnanolone (P3beta5beta), pregnenolone, estradiol (including their polar conjugates), and additional steroids were measured in 16 women in the follicular and luteal phases of the menstrual cycle using gas chromatography/mass spectrometry and RIA for the analysis. Linear models and Spearman's correlations were used for data evaluation. RESULTS AND DISCUSSION: The levels of conjugated PI were from one to almost three orders of magnitude higher in comparison with the free steroids. The results indicate that a substantial proportion of the progesterone is metabolized in the sequence progesterone-->5beta-dihydroprogesterone-->P3alpha5beta-->conjugated P3alpha5beta. The sulfation of PI and particularly of P3alpha5beta moderates the levels of free PI and restrains estradiol biosynthesis via progesterone degradation. PI including the conjugates reflected changing progesterone formation during the menstrual cycle. In the follicular phase, the positive correlation with conjugated pregnenolone, the independence of progesterone, and the negative age relationships of PI indicate their adrenal origin. The dependence on progesterone and the independence of conjugated pregnenolone suggest a gonadal source of PI in the luteal phase. The neuroactivating PI prevailed over neuroinhibiting PI.

• MeSH
• Dehydroepiandrosterone blood   MeSH
• Adult MeSH
• Estradiol blood   MeSH
• Follicular Phase MeSH
• Isomerism MeSH
• Humans MeSH
• Luteal Phase MeSH
• Gas Chromatography-Mass Spectrometry MeSH
• Pregnanolone blood   chemistry   MeSH
• Pregnenolone blood   MeSH
• Progesterone blood   MeSH
• Receptors, GABA-A drug effects   MeSH
• Aging MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Dehydroepiandrosterone MeSH
• Estradiol MeSH
• Pregnanolone MeSH
• Pregnenolone MeSH
• pregnenolone sulfate MeSH Browser
• Progesterone MeSH
• Receptors, GABA-A MeSH