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Type A receptors for GABA (GABA(A) receptors) that contain the delta subunit are located predominantly at extrasynaptic sites and are implicated in modulation of neuronal excitability through tonic inhibition. We have examined the effects of chronic exposure to and subsequent withdrawal of progesterone or the progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THPROG) on expression of the delta subunit of GABA(A) receptors and on receptor function in cultured rat hippocampal neurons. Progesterone treatment for 1 day increased the amounts of both delta subunit mRNA and protein, whereas such treatment for 6 days induced marked decreases in the abundance of both the mRNA and protein. Subsequent progesterone withdrawal up-regulated expression of the delta subunit, which was significantly increased at 9-12 h after withdrawal. These effects of progesterone were mimicked by 3alpha,5alpha-THPROG and blocked by the 5alpha-reductase inhibitor finasteride. They were also accompanied by parallel changes in the function of GABA(A) receptors in hippocampal neurons. These results show that chronic exposure to and withdrawal of progesterone induce differential effects on both expression of the delta subunit of GABA(A) receptors and receptor function that are mediated by 3alpha,5alpha-THPROG. They are consistent with the notion that this progesterone metabolite plays a key physiological role in modulation of GABAergic synapses.

Plasma concentrations of neuroactive steroids in men with panic disorder (PD) were measured to evaluate their relations to psychopathology both before and during treatment. Participants comprised 13 men with PD and 10 normal controls. Patients were evaluated while drug-free as well as after 1 and 2 months of paroxetine therapy. Psychopathology was assessed by the State-Trait Anxiety Inventory (STAI), the Panic-Associated Symptom Scale, and the Fear Questionnaire total score. Plasma concentrations of steroids were measured by radioimmunoassay. The plasma concentrations of progesterone and dehydroepiandrosterone were greater in drug-free patients than in controls, whereas those of allopregnanolone and tetrahydrodeoxycorticosterone did not differ between the two groups. Paroxetine treatment for 2 months significantly increased the plasma concentration of allopregnanolone but did not affect those of the other steroids. At 2 months of therapy, allopregnanolone concentrations in patients were significantly greater than those in controls. The plasma concentrations of progesterone and tetrahydrodeoxycorticosterone correlated with the STAI state score in patients before treatment. Our data suggest that neuroactive steroids may play a role in PD in men.

Neurosteroids are physiological regulators of anxiety in experimental animals, but there are no data for humans about the modulatory effects of the hormones on normal aspects of this emotional parameter. Plasma concentrations of four neurosteroids, pregnenolone, progesterone (PROG), allopregnanolone and tetrahydrodeoxycorticosterone, suggested to be major anxiety regulators in experimental animals, were measured in a group of 58 physically and psychologically normal adult male subjects. In parallel, trait (genotypical) and state (phenotypical) anxiety scores were measured by the State-Trait Anxiety Inventory. The possible correlations between the hormonal secretions and the psychological parameters were statistically analyzed. The neurosteroid concentrations and the anxiety scores of the probands were within the ranges of normality according to data of the literature and our own. PROG concentrations correlated significantly with state anxiety scores. These data suggest that neurosteroids may physiologically modulate anxiety not only in experimental animals but also in humans., (Copyright 2004 S. Karger AG, Basel)

Evidence that neurosteroids have anxiolytic effects in animal models of anxiety has suggested that alterations of neurosteroid secretion might be implicated in the pathogenetic mechanisms of anxiety disorders in humans. In 25 female patients with panic disorder (PD) and 11 healthy female controls, we measured plasma concentrations of progesterone (PROG), pregnenolone (PREG), allopregnanolone (3alpha,5alpha-tetrahydroprogesterone=3alpha,5alpha-THPROG), dehydroepiandrosterone (DHEA) and tetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) during a drug-free month and during the following month of paroxetine therapy. The neurosteroids were measured during the early follicular phase, the mid-luteal phase and the premenstrual phase of both months (days 7, 22 and 27 from the beginning of the cycle). Significantly higher levels in patients than controls were found in PROG during the mid-luteal phase of both months, PREG in the premenstrual phase in the drug-free month, 3alpha,5alpha-THPROG during the follicular phase of the drug-free month and during the premenstrual phase of the therapy month, and 3alpha,5alpha-THDOC during the premenstrual phases of both months. DHEA levels did not differ in patients and controls. These results suggest that neurosteroids in PD are hypersecreted, possibly as an attempt to counteract the anxiogenic underlying hyperactivity of the hypothalamo-pituitary-adrenal axis and to improve a reduced GABA(A) receptor sensitivity.

The effect of endogenous 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG) on the modulation of mesocortical dopamine extracellular concentration by ethanol was investigated by microdialysis in rats. Intraperitoneal injection of progesterone (5 mg/kg, once a day for 5 days) increased the cortical content of 3alpha,5alpha-TH PROG and potentiated the biphasic effect of acute intraperitoneal administration of ethanol on dopamine content. A dose of ethanol (0.25 g/kg) that was ineffective in naïve rats induced a 55% increase in dopamine extracellular concentration in rats pretreated with progesterone. This increase was similar to that induced by a higher dose (0.5 g/kg) of ethanol in naïve rats. Administration of ethanol at 0.5 g/kg to progesterone-pretreated rats inhibited dopamine content by an extent similar to that observed with an even higher dose (1 g/kg) in naïve rats. The administration of the 5alpha-reductase inhibitor finasteride (25 mg/kg, subcutaneous), together with progesterone, prevented the effects of the latter, both on the cortical concentration of 3alpha,5alpha-TH PROG and on the modulation by ethanol of dopamine content. These data suggest that 3alpha,5alpha-TH PROG contributes to the action of ethanol on the mesocortical dopaminergic system. They also suggest that physiological fluctuations in the brain concentrations of neuroactive steroids associated with the oestrous cycle, menopause, pregnancy and stress may alter the response of mesocortical dopaminergic neurons to ethanol.

The influence of the estrous cycle on dopamine levels in the rat medial prefrontal cortex under basal and ethanol-stimulated conditions was evaluated by microdialysis. The basal dopamine concentration in the dialysate varied markedly during the estrous cycle, being highest in estrus and lowest in proestrus. Furthermore, a challenge intraperitoneal administration of ethanol (0.5 g/kg) induced a significant increase in dopaminergic output (+50%) during estrus but had no effect in diestrus or proestrus. Ovariectomy or pretreatment with either finasteride (a 5α-reductase inhibitor) or clomiphene (an estrogen receptor antagonist) prevented this ethanol-induced increase in dopamine concentration. The effect of ethanol was restored in ovariectomized rats by pretreatment with estrogen but not by that with progesterone. Our results thus show that the basal levels of dopamine in the prefrontal cortex are dependent on the phase of the estrous cycle. Furthermore, this dependence appears to be attributable to the effects of ovarian steroid hormones and results in a differential sensitivity of the dopaminergic neurons to ethanol. The hormone-induced changes in the activity of these neurons might contribute to the differences in drug sensitivity and mood state apparent among phases of the estrous cycle and between the sexes.Neuropsychopharmacology (2007) 32, 892–901. doi:10.1038/sj.npp.1301150; published online 12 July 2006 [ABSTRACT FROM AUTHOR]

Type A receptors for GABA (GABAA receptors) that contain the δ subunit are located predominantly at extrasynaptic sites and are implicated in modulation of neuronal excitability through tonic inhibition. We have examined the effects of chronic exposure to and subsequent withdrawal of progesterone or the progesterone metabolite 3α-hydroxy-5α-pregnan-20-one (3α,5α-THPROG) on expression of the d subunit of GABAA receptors and on receptor function in cultured rat hippocampal neurons. Progesterone treatment for 1 day increased the amounts of both d subunit mRNA and protein, whereas such treatment for 6 days induced marked decreases in the abundance of both them RNA and protein. Subsequent progesterone withdrawal up-regulated expression of the d subunit, which was significantly increased at 9-12 h after withdrawal. These effects of progesterone were mimicked by 3α,5α-THPROG and blocked by the 5α-reductase inhibitor finasteride. They were also accompanied by parallel changes in the function of GABAA receptors in hippocampal neurons. These results show that chronic exposure to and withdrawal of progesterone induce differential effects on both expression of the d subunit of GABAA receptors and receptor function that are mediated by 3α,5α-THPROG. They are consistent with the notion that this progesterone metabolite plays a key physiological role in modulation of GABAergic synapses. [ABSTRACT FROM AUTHOR]

In social isolated rats brain and plasma levels of progesterone metabolites, 3α,5α-TH PROG(AP) and 3α,5α-THDOC (THDOC) are reduced while the positive effects of acute stress or acute ethanol on the content of these steroids are enhanced. The ethanol-induced increase in the abundance of AP is more pronounced in the brain than in the plasma of socially isolated rats. Accordingly, social isolation enhanced the effects of ethanol on the amounts of steroidogenic acute regulatory protein (StAR) mRNA and protein in the brain. Moreover, the ability of ethanol to inhibit isoniazid-induced convulsions is greater in socially isolated rats than in group- housed animals, an effect abolished by finasteride, an inhibitor of AP synthesis. In socially isolated rats, the amounts of the α4 and d subunits of the GABAA receptor in the hippocampus were increased, an effect associated to an increase in GABAA receptor-mediated tonic inhibitory currents in granule cells of the dentate gyrus. Ethanol also increased the amplitude of GABAA receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal neurons with a greater potency in slices from socially isolated rats than in those from group-housed, an effect inhibited by finasteride. According with the evidences that separation of rats from their peers during adolescence and adulthood increases voluntary ethanol consumption, isolated rats who had access to increasing concentrations of ethanol for 4 weeks, exhibited higher level of ethanol ingestion than group-housed animals. Voluntary ethanol consumption during social isolation abolished the reduction of the brain and plasma content of AP and THDOC, the enhanced potency of ethanol on mIPSC recorded from CA1 pyramidal neurons, and the acute stress-induced increased in neuroactive steroid concentrations in the cerebral cortex and plasma. These data suggest that the natural preference for ethanol may be related to the effect of this drug on the levels of neuroactive steroids, and that chronic stress due to social isolation may induce plastic adaptation of neuronal systems that contributes to a vulnerability to alcohol abuse. [ABSTRACT FROM AUTHOR]

Summary: Neuroactive steroids modulate anxiety in experimental animals and possibly in humans. The secretion of these compounds has been found to be altered in panic disorder (PD), with such alterations having been suggested to be a possible cause or effect of panic symptomatology. Panic-like attacks can be induced in healthy individuals by administration of panicogenic agents or by physical procedures, and we have now measured the plasma concentrations of neuroactive steroids in such individuals before, during, and after panicogenic inhalation of CO2 in order to investigate whether abnormalities of neuroactive steroid secretion might contribute to the pathogenesis of PD. Fifty-nine psychologically and physically healthy subjects, including 42 women (11 in the follicular phase of the menstrual cycle, 14 in the luteal phase, and 17 taking contraceptive pills) and 17 men, who experienced a panic-like attack on previous exposure to 7% CO2 were again administered 7% CO2 for 20min. Thirty-three of these individuals (responders) again experienced a panic-like attack, whereas the remaining 26 subjects did not (nonresponders). All subjects were examined with the VAS-A and PSL-III-R scales for anxiety and panic symptomatology before and after CO2 inhalation. The plasma concentrations of progesterone, 3α,5α-tetrahydroprogesterone (3α,5α-THPROG=allopregnanolone), 3α,5α-tetrahydrodesoxycorticosterone (3α,5α-THDOC), dehydroepiandrosterone (DHEA), and cortisol were measured 15min and immediately before the onset of CO2 administration as well as immediately, 10, 30, and 50min after the end of CO2 inhalation. Neuroactive steroids were measured in the laboratory of Prof. Biggio in Cagliari, Sardinia, Italy. Neurosteroid levels did not change significantly in both responders and nonresponders before, during, or after CO2 inhalation. These data suggest that neuroactive steroid concentrations before, during, or after CO2 inhalation do not seem to correlate with panic symptomatology during panic-like attacks in subjects not affected by PD, and they therefore do not support the notion that abnormalities in neuroactive steroid secretion are either a cause or an effect of such attacks. [ABSTRACT FROM AUTHOR]

Summary: We investigated whether pregnancy could modify psychological symptoms and whether neuroactive steroids which exert an anti-anxiety effect by acting on the γ-aminobutyric acid (GABA)-A receptors, are modified during pregnancy in young healthy women. Healthy volunteer women in the Department of Obstetrics and Gynecology at Cagliari University participated in the study. They were divided into women with low (group 1, seven subjects) and high (group 2, seven subjects) psychological score by SCL-90 psychometric scale. Age, body mass index and physiological status of pregnancy did not differ between the groups. The subjects were studied before pregnancy during the follicular phase (FP), and the luteal phase (LP) of the menstrual cycle (MC) and four times during pregnancy (at 14th, 22nd, 30th, and 38th week). SCL-90 psychometric scale, circulating levels of progesterone (P4), 3α-hydroxy-5α-pregnan-20-one (allopregnanolone, AP), 3α,21-dihydroxy-5α-pregnan-20-one (allotetrahydrodeoxy-corticosterone, THDOC), cortisol and DHEAS were assayed at each visit. The SCL-90 global score and the intensity of psychological symptoms differ between the groups, but within each group they did not change both during MC and during pregnancy. The DHEAS and cortisol levels did not differ between the groups. DHEAS did not change during the study, whereas cortisol levels increased during pregnancy in both groups. Progesterone, AP, and THDOC levels were higher during LP than during FP and further increased during pregnancy, without any difference between the groups. In conclusion, pregnancy does not seem to interfere with the psychological status of healthy women independently of the psychological basal score. Some neuroactive steroids with anxiolytic activity seem to increase during pregnancy depending on placental function. Their increase could represent some kind of protection against maternal anxiety and stress due to concerns about the pregnancy outcome. [Copyright &y& Elsevier]

Summary: Neuroactive steroids such as 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP) are reduced metabolites of progesterone and are thought to play an important physiological role in local modulation of neuronal excitability by “fine-tuning” the action of γ-aminobutyric acid (GABA) at GABAA receptors. Fluctuations in the concentrations of neuroactive steroids in the brain are also thought to contribute to GABAA receptor plasticity. We here review results from our laboratory related to the regulation of GABAA receptor function and plasticity by changes in the levels of neuroactive steroids during pregnancy and after delivery in rats. Pregnancy is characterized by marked and progressive increases in the plasma and brain concentrations of neuroactive steroids, which are implicated in the changes in mood, anxiety, and other psychiatric states associated with this condition. We have shown that the increases in the brain levels of neuroactive steroids during pregnancy are causally related to changes in the expression of specific GABAA receptor subunits and the function of extrasynaptic GABAA receptors in the hippocampus. [Copyright &y& Elsevier]