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J. Neurochem. (2010) 113, 1285–1295. Gonadal steroids, in particular estradiol, exert important actions during pre- and perinatal periods in the regulation of sexual dimorphism and development of the nervous system. We have now examined the effects of neonatal estradiol administration in female rats on brain concentrations of the neuroactive steroids allopregnanolone and tetrahydrodeoxycorticosterone, expression of GABAA receptor subunits, and behavioral sensitivity to benzodiazepines and allopregnanolone. Administration of β-estradiol 3-benzoate on the day of birth resulted in marked decreases in the concentrations of progesterone and allopregnanolone in the cerebral cortex at 21, 60, and 180 days after birth. The concentrations of tetrahydrodeoxycorticosterone, 17β-estradiol, and dehydroepiandrosterone in the brain at 60 days were not affected by such treatment. Neonatal administration of β-estradiol 3-benzoate also increased the cerebrocortical abundance of α1, α2, and γ2 subunits of the GABAA receptor without affecting that of α3, α4, α5, or δ subunits. Diazepam induced a greater reduction in locomotor activity as well as a more pronounced anxiolytic-like effect in the elevated plus-maze test in rats subjected to neonatal treatment with β-estradiol 3-benzoate than in vehicle-treated controls, while allopregnanolone induced a similar effect in both groups. These effects of estradiol suggest that it plays a major role in regulation both of GABAergic transmission and of the abundance of endogenous modulators of such transmission during development of the central nervous system. [ABSTRACT FROM AUTHOR]

The feeding behaviour of the freshwater polypHydra vulgaris(Cnidaria, Hydrozoa) is modulated by a number of molecules acting as neurotransmitters in other nervous systems. Here we present biochemical and functional evidence of the occurrence of putative NMDA receptors inHydratissues. Saturation experiments showed the presence of one population of binding sites with nanomolar affinity and low capacity for[3H]MK-801. Before equilibrium,[3H]MK-801 binding was increased by the agonists glutamate and glycine as well as by reduced glutathione (GSH).In vivothe glutamate receptor agonist NMDA markedly decreased the duration of the response to GSH. This effect was linearly related to ligand doses in the nanomolar concentration range and was counteracted by either the NMDAR-specific antagonist D-AP5 or by thed-serine antagonist DCKA. When NMDA concentration was increased to 10 or 100 µm, duration of the response to GSH was no longer affected unless the lectin concanavalin A, which prevents receptor desensitization in other systems, was added to the test medium. Simultaneous administration of ineffective doses of NMDA and strychnine, glycine ord-serine, an agonist at the glycine binding site of the NMDA receptor in vertebrate CNS, resulted in a strong reduction of response duration. Both D-AP5 and DCKA suppressed this effect. These results, together with the decrease in response duration produced byd-serine, support the hypothesis that NMDA-like glutamate receptors may occur inHydratissues where they are involved in modulation of the response to GSH with opposite actions to those of GABA and glycine. [ABSTRACT FROM AUTHOR]

γ-Hydroxybutyric acid (GHB), a drug proposed in the treatment of alcohol withdrawal syndrome, increases the cerebrocortical and plasma concentrations of the neuroactive steroids allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC). In the present study, we examined the role of hypothalamic–pituitary–adrenal (HPA) axis in the effect of GHB by measuring the concentrations of these steroids in the brain and plasma of adrenalectomized–orchiectomized (Adx–Orx) rats. The acute administration of GHB (500 mg/kg, i.p.) induced in 30 min an increase in the concentrations of allopregnanolone, THDOC and their precursors pregnenolone and progesterone in different brain areas (cerebral cortex, hypothalamus and cerebellum) and plasma of sham-operated rats but had no effect on the concentrations of these compounds in Adx–Orx rats, suggesting that activation of the HPA axis mediates the effect of GHB on brain and plasma concentrations of neuroactive steroids. Moreover, we evaluated whether repeated exposure of GHB induces tolerance to its steroidogenic effects. Chronic administration of GHB (500 mg/kg, i.p., twice a day for 10 days) to intact animals failed to affect the levels of progesterone, allopregnanolone, or THDOC measured 3 or 48 h after the last drug administration, whereas a challenge injection of GHB or ethanol was still able to increase the concentrations of these steroids in brain and plasma. These results indicate that repeated exposure to GHB fails to induce tolerance or cross-tolerance to the steroidogenic action of GHB or ethanol, respectively. [Copyright &y& Elsevier]

Abstract: Fluctuations in the concentrations of the neuroactive steroid allopregnanolone are thought to influence γ-amino-butyric acid type A (GABAA) receptor gene expression and function. Long-term treatment with ethinyl estradiol (EE) plus levonorgestrel (LNG), two of the most widely used steroids in the hormonal contraceptive pill, decreases allopregnanolone levels in rat cerebral cortex and plasma, alters GABAA receptor expression and induces anxiety-like behavior. We evaluated which component of the hormonal contraceptive pill is responsible for the aforementioned changes. Female rats were injected subcutaneously (s.c.) with EE (0.030mg) or LNG (0.125mg) once a day for 4 weeks. Compared to the respective vehicle-treated control groups, EE decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 76, 72 and 33%, respectively and hippocampal levels by 52, 56 and 50%, respectively. Likewise, LNG decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 75, 68 and 33%, respectively, and hippocampal levels by 55, 65 and 60%, respectively. Administration of LNG, but not EE, increased the abundance of the γ2 subunit peptide in cerebral cortex and hippocampus by 38 and 59%, respectively. Further, LNG, but not EE, decreased the time spent and the number of entries into the open arms of the elevated plus maze by 56 and 43%, respectively, an index of anxiety-like behavior. These results suggest that alterations in GABAA receptor subunit expression and anxiety-like behavior induced by long-term treatment with combined EE/LNG appear to be caused by LNG. Given that both EE and LNG decrease allopregnanolone levels in a similar manner, these results further suggest that changes in allopregnanolone levels are not associated with GABAA receptor expression. [Copyright &y& Elsevier]

Objective: To investigate in healthy eumenorrheic young women whether an oral contraceptive (OC) containing drospirenone (DRSP) (3 mg) + ethinyl estradiol (EE) (30 microg) (DRSP + EE) could modify psychological symptoms and whether it could modify steroids interfering with the gamma-aminobutyric acid (GABA)-A receptors., Design: Clinical study of treated subjects and nontreated controls., Setting: Healthy volunteers in the Department of Obstetrics and Gynecology at Cagliari University., Patient(s): Control group (n = 12) and OC group (n = 10) women with similar age, body mass index, and main outcome measures., Intervention(s): The control group was studied during the first menstrual cycle at the follicular phase (FP) and at the luteal phase (LP) and during the third cycle at the LP; the OC group was studied during the first cycle, as described above, and on day 16-18 of the third cycle of treatment with DRSP + EE., Main Outcome Measure(s): Psychometric scale (SCL-90), DHEAS, P, allopregnanolone (AP), and allotetrahydrodeoxy-corticosterone (THDOC)., Result(s): SCL-90 and DHEAS did not vary throughout the menstrual cycle. P, AP, and THDOC values were higher during the LP than the FP. At the third cycle, in the control group the main outcome measures were similar to those at LP. In the OC group, the SCL-90 global score, the intensity of anxiety and phobic anxiety, the levels of anxiolytic steroids (P, AP, THDOC) and the anxiety-inducing steroid DHEAS were reduced., Conclusion(s): The results suggest beneficial effects of DRSP + EE on psychological symptoms by decreasing DHEAS.