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Other Sleep Modulators
Published in Shojiro Inoué, Biology of Sleep Substances, 2020
Mendelson et al.112 reported that an adrenal mineralocorticosteroid metabolite, 3-α,5-α-tetrahydrodeoxycorticosterone (THDOC, 10 mg/kg; see Figure 9) i.p. injected in the light period significantly reduced sleep latency and enhanced SWS for a 2-h postinjection, recording period in male rats. No influence was found on PS by the treatment. Since THDOC has barbiturate-like properties in vitro113 and anxiolytic activities in vivo, the hypnotic effect may be mediated by actions at the GABA-BZ-barbiturate-receptor complex. It is suggested that THDOC or similar steroids may play some role in sleep regulation.
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
Though there is evidence of underlying changes in GABAA receptor function in PMDD, the question of what causes these phenomena remains. One plausible mechanism is that GABAA receptors may be regulated by endogenous modulators, such as the neuroactive metabolites of steroid hormones. Generally, steroid hormones, such as corticosterone and progesterone, exert their effects over a relatively long time by acting as transcription factors that regulate protein expression. These compounds can, however, also be further processed into neuroactive metabolites, which are known as neurosteroids since they have rapid actions at nerve cell membrane receptors and are synthesized in the brain.53 Neuroactive steroids include tetrahydrodeoxycorticosterone (THDOC), a derivative of corticosterone, and allopregnanolone and pregnanolone (3a-hydroxγ-5α-pregnane-20-one and 3a-hydroxγ-5β-pregnane-20-one, respectively), which are neuroactive metabolites of progesterone.
Steroid Metabolism in the Brain: Role in Sexual Differentiation
Published in Akira Matsumoto, Sexual Differentiation of the Brain, 2017
Paola Negri-Cesi, Angelo Poletti, Luciano Martini, Flavio Piva
The 3α-HSD catalyzes the 3-hydroxylation of 5α-reduced steroids such as DHT, DHP, and gluco- and minerocorticoids to the corresponding tetrahydroderivatives. This enzyme is widely distributed in the adult rat brain with the highest levels in the olfactory bulb, and its main localization is in the type 1 astrocytes (see Reference 117 for references). To the authors’ knowledge, the ontogenetic profile of this enzyme has not been studied yet; however, indirect evidence obtained in neuronal and glial cell cultures obtained from fetal/neonatal brain indicates that it is already functional around the time of birth.118 The presence of this enzyme might be of paramount importance for linking the steroidal effects occurring via the classical intracellular steroid receptors with other effects of steroids due to the binding of their metabolites to neurotransmitter receptors. It is indeed known that the 3α-HSD is responsible for the formation of 3α-hydroxy, 5α-pregnan-20-one (allopregnanolone or tetrahydroprogesterone, THP), and of 3α, 21-dihydroxy-5α-pregnan-20-one (tetrahydrodeoxycorticosterone, THDOC), which are two potent neurally active steroids. These two 5α-reduced-3α-hydroxylated compounds are unable to interact with the classical intracellular receptors for progesterone and for the minerocorticoids, but their action may be mediated by the GABAA receptor.25 The activation of this receptor may explain their potent anesthetic / anxiolytic activities. The peak of expression of 5α-R type 2 around the time of birth might therefore be crucial in providing the 3α-HSD with possible precursors for the final formation of active anxiolytic/anesthetic steroids involved in modulating the stress responses which occur at the time of parturition, i.e., a time at which also progesterone levels are particularly elevated.25,119 It is interesting that during gestation the GABAA receptors are highly sensitive to modulators,120 and that the hormonal manipulations which alter the sexual differentiation of the perinatal brain (castration in males, testosterone administration in females) modify the normal response of the animals to stressor stimuli.121
The influence of hormonal contraception on depression and female sexuality: a narrative review of the literature
Published in Gynecological Endocrinology, 2022
Laura Buggio, Giussy Barbara, Federica Facchin, Laura Ghezzi, Dhouha Dridi, Paolo Vercellini
COCs can also negatively affect some aspects of female sexuality, such as desire, arousal, lubrication, and orgasm, because of a specific central effect on different brain regions, including the mediobasal hypothalamus and the arcuate nucleus, where sex hormones might modify the complex relationship between neurotransmitters and neuropeptides [96]. It has been demonstrated that the nervous system expresses two enzymes (the steroidogenic acute regulatory [StAR] protein and cytochrome P450scc) required for the synthesis of neuroactive steroids, such as for instance progesterone, dehydroepiandrosterone (DHEA), 17β-estradiol, and 5α-reduced steroids, 3α,5α-tetrahydrodeoxycorticosterone (THDOC), 3α,5α-tetrahydroprogesterone (allopregnanolone) and 3α,5β-tetrahydroprogesterone (pregnanolone) [97,98]. Steroidogenic enzymes and neurosteroids are concentrated in specific areas of the brain, including those involved in sexual behavior and functioning, like the amygdala, olfactory bulb, and hypothalamus [99]. Preclinical studies suggest that hormonal contraceptives can influence neurosteroids, neurotransmitters, and consequently emotional and sexual behaviors. A decreased concentration of some neurosteroids (such as allopregnanolone) might contribute to the negative modifications in sexuality reported by several women taking hormonal contraceptives [100,101].
Change in gene expression levels of GABA, glutamate and neurosteroid pathways due to acoustic trauma in the cochlea
Published in Journal of Neurogenetics, 2021
Meltem Cerrah Gunes, Murat Salih Gunes, Alperen Vural, Fatma Aybuga, Arslan Bayram, Keziban Korkmaz Bayram, Mehmet Ilhan Sahin, Muhammet Ensar Dogan, Sevda Yesim Ozdemir, Yusuf Ozkul
PS is also a noncompetitive GABA-A receptor antagonist (Majewska, 1992). It is thought PS induces a decrease in GABA-A receptor channel opening frequency (Akk et al., 2001). We found a statistically significant decrease in both Sult1a1 and Gabra1 expressions in Post-AT(15) group, but no correlation was found. Some neurosteroids such as allopregnanolone (3α-OH-5α-pregnan-20-one), 5α- androstane-3α, 17α-diol, and 3α5α-tetrahydrodeoxycorticosterone (3α5α-THDOC) are also positive modulators of GABA-A receptors and the key step of synthesis of these positive modulators is also catalyzed by Cyp11a1 (Wang, 2011). Although Cyp11a1 gene expression was decreased, the ratio of negative (pregnenolone sulfate)/positive GABA-A receptor modulator (allopregnanolone, 3α5α-THDOC) may have been shifted to the direction of positive modulation. Therefore, there was no correlation between Cyp11a1, Sult1a1 and Gabra1. However, Cyp11a1, Sult1a1 and Gad1 gene expression were correlated with each other. Gad1 encodes the enzyme that catalyzes the conversion of glutamic acid to GABA, the main inhibitory neurotransmitter (Erlander, Tillakaratne, Feldblum, Patel, & Tobin, 1991). PS and other neurosteroids may have affected the GABAergic pathway via a decreased synthesis of GABA in our study because there was also no correlation between Cyp11a1 and Sult1a1 genes and the Slc6a1 gene which removes GABA from the synaptic cleft to presynaptic terminals (Hirunsatit et al., 2009).
GABA(A) receptor-targeted drug development -New perspectives in perioperative anesthesia
Published in Expert Opinion on Drug Discovery, 2019
Bernd Antkowiak, Gerhard Rammes
Most of the neurosteroids investigated are PAMs on GABAA receptors. Low concentrations (10–100 nmol/L) of 3α,5α-THPROG strongly enhances the net chloride current through α1β1γ2 or α3β1γ2 containing receptors, whereas equivalent receptors that incorporate the α2-, α4- and α5-subunits require threefold to tenfold higher concentrations for potentiation [143]. Receptors with γ1-subunits are less sensitive to 3α,5α-THPROG than equivalent receptors that express either γ2- or γ3-subunits [143,173]. As detailed above, receptors assembled with a δ subunit dramatically augments the GABA-enhancing actions of 3α,5α-THPROG. Even though less detailed analysed, tetrahydrodeoxycorticosterone (3α,5α-THDOC) and pregnanolone (3α,5β-THPROG) selectively enhance tonic GABAergic conductance [152,170,174]. Moreover, 3α,5α-THDOC applied at higher concentrations (>1 µM), also exhibits agonistic action at the GABA receptor [175,176].