The past decade has brought many advances in our understanding of GABA A receptor-mediated ethanol action in the central nervous system. We now know that specific GABA A receptor subtypes are sensitive to ethanol at doses attained during social drinking while other subtypes respond to ethanol at doses attained by severe intoxication. Furthermore, ethanol increases GABAergic neurotransmission through indirect effects, including the elevation of endogenous GABAergic neuroactive steroids, presynaptic release of GABA, and dephosphorylation of GABA A receptors promoting increases in GABA sensitivity. Ethanol's effects on intracellular signaling also influence GABAergic transmission in multiple ways that vary across brain regions and cell types. The effects of chronic ethanol administration are influenced by adaptations in GABA A receptor function, expression, trafficking, and subcellular localization that contribute to ethanol tolerance, dependence, and withdrawal hyperexcitability. Adolescents exhibit altered sensitivity to ethanol actions, the tendency for higher drinking and longer lasting GABAergic adaptations to chronic ethanol administration. The elucidation of the mechanisms that underlie adaptations to ethanol exposure are leading to a better understanding of the regulation of inhibitory transmission and new targets for therapies to support recovery from ethanol withdrawal and alcoholism.

The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of ␥-aminobutyric acid type A (GABA A ) receptors in the brain during pregnancy and after delivery was investigated in rats. In contrast with plasma, where all steroids increased in parallel, the kinetics of changes in the cerebrocortical concentrations of progesterone, allopregnanolone (AP), and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy. Progesterone was already maximally increased between days 10 and 15, whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19. The stimulatory effect of muscimol on 36 Cl ؊ uptake by cerebrocortical membrane vesicles was decreased on days 15 and 19 of pregnancy and increased 2 days after delivery. Moreover, the expression in cerebral cortex and hippocampus of the mRNA encoding for ␥2L GABA A receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also ␣1,␣2, ␣3, ␣4, ␤1, ␤2, ␤3, and ␥2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5␣-reductase inhibitor, to pregnant rats reduced the concentrations of AP more in brain than in plasma as well as prevented the decreases in both the stimulatory effect of muscimol on 36 Cl ؊ uptake and the decrease of ␥2L mRNA observed during pregnancy. These results indicate that the plasticity of GABA A receptors during pregnancy and after delivery is functionally related to f luctuations in endogenous brain concentrations of AP whose rate of synthesis͞metabolism appears to differ in the brain, compared with plasma, in pregnant rats.An important feature of ␥-aminobutyric acid type A (GABA A ) receptors in rat brain is their plasticity in response to exposure to brief or long-lasting physiological stimuli or to long-term pharmacological treatments. The kinetic characteristics of the various binding sites located on the GABA A receptor, as well as the density and function of these receptors in different areas of the rat brain, are affected by acute stressful stimuli (handling, foot shock, swimming), postnatal development, aging, kindling, and long-term administration of anxiolytic, hypnotic, or anticonvulsant drugs (1-6). Although recent studies have suggested that some of these changes may be mediated at the level of expression of receptor subunit genes (7-10), the chemical or molecular events that underlie such rapid, shortterm, or persistent changes in the density and affinity of binding sites associated with GABA A receptors, as well as in the function of the receptor complex, remain to be characterized.Neurosteroids accumulate in the mammalian brain in a manner that is, at least in part, independent of the peripheral tissues (adrenal glands and gonads) that synthesize these compounds (11). Systemic administration of progesterone or its metabolites 3␣-hydroxy-5␣-pregnan-20-one (allopregnanolone, AP) and 3␣,21-dihydroxy-5␣-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC) induces an...

The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n = 9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change = 10.38) compared with patients receiving placebo (mean change = 2.33), p = 0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs = 0.81, p = 0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs = 0.74, p = 0.046). In addition, baseline pregnenolone (rs = −0.76, p = 0.037), pregnenolone sulfate (rs = − 0.83, p = 0.015), and allopregnanolone levels (rs = −0.83, p = 0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs = 0.74, p <0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.

Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the γ-amino-butyric type A (GABAA) receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases. Neuroactive steroids regulate many physiological functions such as stress response, puberty, ovarian cycle, pregnancy and reward. Their levels are altered in several neuropsychiatric and neurologic diseases and both preclinical and clinical studies emphasise a therapeutic potential of neuroactive steroids for these diseases, whereby symptomatology ameliorates upon restoration of neuroactive steroid concentrations. However, direct administration of neuroactive steroids has several challenges, including pharmacokinetics, low bioavailability, addiction potential, safety and tolerability that limit its therapeutic use. Therefore, modulation of neurosteroidogenesis to restore the altered endogenous neuroactive steroid tone may represent a better therapeutic approach. This review summarizes recent approaches that target the neuroactive steroid biosynthetic pathway at different levels in order to promote neurosteroidogenesis. These include modulation of neurosteroidogenesis through ligands of the translocator protein 18 kDa (TSPO), and the pregnane xenobiotic receptor (PXR), as well as targeting of specific neurosteroidogenic enzymes like 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) or P450 side chain cleavage (P450scc). Enhanced neurosteroidogenesis through these targets may be beneficial for neurodegenerative diseases such as Alzheimer's disease and age-related dementia, but also for neuropsychiatric diseases, including alcohol use disorders.