Sex-dependent changes of hippocampal synaptic plasticity and cognitive performance in C57BL/6J mice exposed to neonatal repeated maternal separation.

The repeated maternal separation (RMS) is a useful experimental model useful in rodents to study the long-term influence of early-life stress on brain neurophysiology. We here investigated the influence of RMS exposure on hippocampal inhibitory and excitatory synaptic transmission, long-term synaptic plasticity and the related potential alterations in learning and memory performance in adult male and female C57Bl/6J mice. Mice were separated daily from their dam for 360 min, from postnatal day 2 (PND2) to PND17, and experiments were performed at PND 60. Patch-clamp recordings in hippocampal CA1 pyramidal neurons revealed a significant enhancement of GABAergic miniature IPSC (mIPSC) frequency, and a decrease in the amplitude of glutamatergic mEPSCs in male mice exposed to RMS. Only a slight but significant reduction in the amplitude of GABAergic mIPSCs was observed in females exposed to RMS compared to the relative controls. A marked increase in long-term depression (LTD) at CA3-CA1 glutamatergic synapses and in the response to the CB1r agonist win55,212 were detected in RMS male, but not female mice. An impaired spatial memory and a reduced preference for novelty was observed in males exposed to RMS but not in females. A single injection of ß-ethynyl estradiol at PND2, prevented the changes observed in RMS male mice, suggesting that estrogens may play a protective role early in life against the exposure to stressful conditions. Our findings strengthen the idea of a sex-dependent influence of RMS on long-lasting modifications in synaptic transmission, effects that may be relevant for cognitive performance.

Radiosynthesis and in vivo evaluation of two imidazopyridineacetamides, [(11)C]CB184 and [ (11)C]CB190, as a PET tracer for 18 kDa translocator protein: direct comparison with [ (11)C](R)-PK11195.

OBJECTIVE: We report synthesis of two carbon-11 labeled imidazopyridines TSPO ligands, [(11)C]CB184 and [(11)C]CB190, for PET imaging of inflammatory process along with neurodegeneration, ischemia or brain tumor. Biodistribution of these compounds was compared with that of [(11)C]CB148 and [(11)C](R)-PK11195. METHODS: Both [(11)C]CB184 and [(11)C]CB190 having (11)C-methoxyl group on an aromatic ring were readily prepared using [(11)C]methyl triflate. Biodistribution and metabolism of the compounds were examined with normal mice. An animal PET study using 6-hydroxydopamine treated rats as a model of neurodegeneration was pursued for proper estimation of feasibility of the radioligands to determine neuroinflammation process. RESULTS: [(11)C]CB184 and [(11)C]CB190 were obtained via O-methylation of corresponding desmethyl precursor using [(11)C]methyl triflate in radiochemical yield of 73 % (decay-corrected). In vivo validation as a TSPO radioligand was carried out using normal mice and lesioned rats. In mice, [(11)C]CB184 showed more uptake and specific binding than [(11)C]CB190. Metabolism studies showed that 36 % and 25 % of radioactivity in plasma remained unchanged 30 min after intravenous injection of [(11)C]CB184 and [(11)C]CB190, respectively. In the PET study using rats, lesioned side of the brain showed significantly higher uptake than contralateral side after i.v. injection of either [(11)C]CB184 or [(11)C](R)-PK11195. Indirect Logan plot analysis revealed distribution volume ratio (DVR) between the two sides which might indicate lesion-related elevation of TSPO binding. The DVR was 1.15 ± 0.10 for [(11)C](R)-PK11195 and was 1.15 ± 0.09 for [(11)C]CB184. CONCLUSION: The sensitivity to detect neuroinflammation activity was similar for [(11)C]CB184 and [(11)C](R)-PK11195.

Carborane-conjugated 2-quinolinecarboxamide ligands of the translocator protein for boron neutron capture therapy.

Potential boron neutron capture therapy (BNCT) agents have been designed on the basis of the evidence about translocator protein (TSPO) overexpression on the outer mitochondrial membrane of tumor cells. The structure of the first TSPO ligand bearing a carborane cage (compound 2d) has been modified in order to find a suitable candidate for in vivo studies. The designed compounds were synthesized and evaluated for their potential interaction with TSPO and tumor cells. In vitro biological evaluation showed in the case of fluoromethyl derivative 4b a nanomolar TSPO affinity very similar to that of 2d, a significantly lower cytotoxicity, and a slightly superior performance as boron carrier toward breast cancer cells. Moreover, compound 4b could be used as a ¹9F magnetic resonance imaging (MRI) agent as well as labeled with ¹¹C or ¹8F to obtain positron emission tomography (PET) radiotracers in order to apply the "see and treat" strategy in BNCT.

Neonatal exposure to estradiol in rats influences neuroactive steroid concentrations, GABAA receptor expression, and behavioral sensitivity to anxiolytic drugs.

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 GABA(A) receptor subunits, and behavioral sensitivity to benzodiazepines and allopregnanolone. Administration of beta-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, 17beta-estradiol, and dehydroepiandrosterone in the brain at 60 days were not affected by such treatment. Neonatal administration of beta-estradiol 3-benzoate also increased the cerebrocortical abundance of alpha(1), alpha(2), and gamma(2) subunits of the GABA(A) receptor without affecting that of alpha(3), alpha(4), alpha(5), or delta 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 beta-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.

Neuroactive steroids after estrogen exposure in depressed postmenopausal women treated with sertraline and asymptomatic postmenopausal women.

Neuroactive steroids (NAS) allopregnanolone (ALLO), Allotetrahydrodeoxycorticosterone (THDOC) and dehydroepiandrosterone (DHEA) are important in the regulation of mood and behavior. Knowledge about these steroids in postmenopausal depression and the effect of estrogen on NAS is lacking. We elected to determine if there were differences in NAS between postmenopausal depressed women and age matched controls. We also investigated the effect of estradiol on NAS in post menopausal depressed women receiving a selective serotonin reuptake inhibitor (SSRI), and in non-depressed postmenopausal controls. As part of a previously published double blind study on estrogen acceleration of antidepressant action, post menopausal women with major depression receiving sertraline and healthy non depressed controls were randomized to transdermal estrogen patch 0.1 mg or placebo. NAS were measured at baseline and after 10 weeks of treatment. Depressed subjects were treated with sertraline 50 mg/day to 100 mg/day for 9 weeks. At the baseline and after treatment ALLO and DHEA were significantly lower in depressed women compared to controls. Although all depressed subjects experienced a positive clinical response, estrogen administration was not associated with changes in NAS in either the depressed or the asymptomatic postmenopausal women. The lower ALLO and DHEA in postmenopausal depressed women suggests that symptoms of depression may be influenced by the synthesis or fluctuation of these NAS. Estradiol exposure did not alter ALLO, DHEA, or THDOC, implying these NAS are unlikely to play a role in any mood changes in post menopausal women given estrogen therapy.

GABA(A) receptor function and gene expression during pregnancy and postpartum.

Neuroactive steroids such as 3alpha,5alpha-THP are reduced metabolites of progesterone and are considered to play an important physiological role to locally modulate neuronal excitability by "fine-tuning" the action of GABA acting at GABA(A) receptors (GABA(A)-Rs). In different brain regions, such as the hippocampus, different subpopulations of nerve cells exhibit two components of inhibitory GABAergic transmission: a phasic component mediated by synaptic GABA(A)-Rs, and a tonic component mediated by "ambient" GABA acting at extrasynaptic GABA(A)-Rs mainly containing the delta subunit and endowed with a higher sensitivity to neuroactive steroids compared to synaptic receptors. It is also well accepted that fluctuations in brain neuroactive steroid levels may result in plastic changes of GABA(A)-Rs. In this article we review some of our results obtained with the model of pregnancy in rats. Pregnancy, in fact, is characterized by a marked and progressive increase in plasma and brain levels of neuroactive steroids which could contribute to changes in mood, anxiety as well as other psychiatric conditions. Such elevation in brain neuroactive steroid concentrations during pregnancy, in turn, is accompanied by alterations in both gene expression and function of synaptic and extrasynaptic GABA(A)-Rs in the hippocampus as well as other areas.

Plasticity and function of extrasynaptic GABA(A) receptors during pregnancy and after delivery.

Neuroactive steroids such as 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-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 gamma-aminobutyric acid (GABA) at GABA(A) receptors. Fluctuations in the concentrations of neuroactive steroids in the brain are also thought to contribute to GABA(A) receptor plasticity. We here review results from our laboratory related to the regulation of GABA(A) 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 GABA(A) receptor subunits and the function of extrasynaptic GABA(A) receptors in the hippocampus.

Reduced serum level of THDOC, an anticonvulsant steroid, in women with perimenstrual catamenial epilepsy.

PURPOSE: Seizure exacerbation in catamenial epilepsy (CE) is associated with the decrease in progesterone secretion and increase in estradiol secretion during the premenstrual period. Moreover, experimental evidence suggests that tetrahydrodeoxycorticosterone (THDOC), a positive modulator of the type A receptor for gamma-aminobutyric acid (GABA), and dehydroepiandrosterone sulfate (DHEAS), a negative modulator of this receptor, might play a crucial role in modulating seizure frequency during the menstrual cycle. Following these studies it seems of interest to investigate possible variations, among other hormonal parameters, of THDOC and DHEAS in CE patients. METHODS: The serum concentrations of progesterone (P4), pregnenolone, allopregnanolone (AP), THDOC, DHEAS, cortisol, and DHEAS/cortisol ratio were measured throughout the menstrual cycle at the 7th, 11th, 15th, 19th, 23rd, and 27th day from the onset of spontaneous menstrual blood loss in young premenopausal women with CE (n = 17) and age-matched controls (n = 13). RESULTS: At each time of the study, the serum concentration of THDOC and the DHEAS/cortisol ratio were lower (p < 0.05) in women with CE than in control women. The concentrations of P4, pregnenolone, and AP did not differ between the two groups of subjects. CONCLUSIONS: The reduced serum concentration of THDOC and the reduced DHEAS/cortisol ratio detected throughout the menstrual cycle in women with CE might play a role in CE. Moreover, the peculiar pattern of CE seizure exacerbation might suggest that these neuroendocrine variations are worth investigating in other epileptic syndromes, particularly in those characterized by relevant and uncontrolled variations in seizure frequency.

N-benzyl-2-(6,8-dichloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N-(6-(7-nitrobenzo[c][1,2,5]oxadiazol-4-ylamino)hexyl)acetamide as a new fluorescent probe for peripheral benzodiazepine receptor and microglial cell visualization.

The aim of this work was to develop new fluorescent probes for the localization and function of the peripheral benzodiazepine receptor (PBR). This receptor is primarily expressed on the mitochondria, and it is overexpressed in a variety of different states including glioma, breast cancer, Alzeheimer's disease, and activated microglia. For the mentioned purpose, imidazopyridine and imidazopyrimidine compounds 5-20 were synthesized, and their affinity for PBR was determined. Although some intrinsically fluorescent imidazopyrimidine compounds 12-20 possess good binding affinity, they cannot be used for visualizing PBR due to their unfavorable fluorescence characteristics. Among the imidazopyridine-7-nitrofurazan conjugates 5-11, compound 10 was the most active, and it was found to stain live Ra2 microglial cells effectively. An in vivo biodistribution study carried out on compound 10 showed that this imidazopyridine derivative, injected in the carotid artery, is able to penetrate to liver parenchyma, whereas fluorescein isothiocyanate labeled dextran (FITC-dextran), used as a control dye, hardly penetrated from blood vessels to tissues. On the other hand, as for the distribution to brain, the patterns of staining with 10 and FITC-dextran are similar, indicating that both of them hardly penetrate into the brain because of the existence of the blood-brain barrier. The obtained results indicate that compound 10 represents a new useful fluorescent probe for visualization of activated microglia and PBR.

Estrous cycle-dependent changes in basal and ethanol-induced activity of cortical dopaminergic neurons in the rat.

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 5alpha-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.

Changes in expression of the delta subunit of the GABA (A) receptor and in receptor function induced by progesterone exposure and withdrawal.

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.

Increased neuroactive steroid concentrations in women with bipolar disorder or major depressive disorder.

Changes in the plasma concentrations of neuroactive steroids have been associated with various neuropsychiatric disorders. However, the possible role of neuroactive steroids in bipolar disorder (BD) has remained unknown. We therefore determined the plasma levels of neuroactive steroids during the luteal phase of the menstrual cycle in women with BD or major depressive disorder (MDD). The plasma concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THPROG), 3alpha,21-dihydroxy-5alpha-pregnan-20-one, progesterone, and cortisol were determined in 17 outpatients with BD, 14 outpatients with MDD, and 16 healthy control subjects. All patients were in a state of well-being and without relapse or recurrence for at least 3 months. Plasma concentrations of progesterone and 3alpha,5alpha-THPROG were significantly greater in patients than in controls, also being higher in BD patients than in MDD patients. Drug-free patients with BD or MDD showed similar differences in steroid concentrations relative to controls, as did drug-treated patients. Comorbidity with panic disorder, obsessive-compulsive disorder, or eating disorder had no effect on the association of mood disorders with steroid concentrations. Women with BD or MDD in a state of well-being showed higher plasma concentrations of progesterone and 3alpha,5alpha-THPROG in the luteal phase than did healthy controls. These differences did not seem to be attributable simply to drug treatment or to comorbidity with other psychiatric conditions in the patients.

Oral contraceptives and neuroactive steroids.

A deregulation in the peripheral and brain concentrations of neuroactive steroids has been found in certain pathological conditions characterized by emotional or affective disturbances, including major depression and anxiety disorders. In this article we summarize data pertaining to the modulatory effects of oral contraceptive treatment on neuroactive steroids in women and rats. Given that the neuroactive steroids concentrations are reduced by oral contraceptives, together with the evidence that a subset of women taking oral contraceptives experience negative mood symptoms, we propose the use of this pharmacological treatment as a putative model to study the role of neuroactive steroids in the etiopathology of mood disorders. Moreover, since neuroactive steroids are potent modulators of GABA(A) receptor function and plasticity, the treatment with oral contraceptives might also represent a useful experimental model to further investigate the physiological role of these steroids in the modulation of GABAergic transmission.

Observational study on the stability of the psychological status during normal pregnancy and increased blood levels of neuroactive steroids with GABA-A receptor agonist activity.

We investigated whether pregnancy could modify psychological symptoms and whether neuroactive steroids which exert an anti-anxiety effect by acting on the gamma-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), 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone, AP), 3alpha,21-dihydroxy-5alpha-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.

Neurosteroids in nicotine and morphine dependence.

RATIONALE: Neurosteroids are implicated in various stages of drug dependence, including the acquisition phase, tolerance, and withdrawal. The neurosteroid allopregnanolone is also able to substitute for drugs with abuse potential and possesses reinforcing properties. OBJECTIVES: The effects of acute treatment with, and discontinuation of, chronic exposure to nicotine or morphine on the concentrations of allopregnanolone and its precursors, pregnenolone and progesterone, in the cerebral cortex and plasma of rats were investigated. The role of the hypothalamic-pituitary-adrenal (HPA) axis in, and the development of tolerance to, such effects were also examined. METHODS: Nicotine or morphine was administered acutely or chronically, and withdrawal syndrome was induced by spontaneous discontinuation of drug treatment or by administration of a corresponding receptor antagonist (mecamylamine and naloxone, respectively). Neurosteroids were extracted from the cerebral cortex and plasma, fractionated by high-performance liquid chromatography, and quantitated by radioimmunoassay. RESULTS: Acute intraperitoneal administration of nicotine (0.3-2 mg kg-1) or morphine (5-30 mg kg-1) induced dose- and time-dependent increases in the cerebrocortical and plasma concentrations of pregnenolone, progesterone, and allopregnanolone. The effects of both drugs were abolished by adrenalectomy-orchiectomy. Spontaneous or naloxone-precipitated morphine withdrawal and mecamylamine-precipitated (but not spontaneous) nicotine withdrawal also increased neurosteroid concentrations in the brain and plasma. A challenge dose of nicotine or morphine, administered 14 or 24 h after the last drug injection in chronic ally treated rats, failed to increase cerebrocortical neurosteroid concentrations. CONCLUSIONS: Changes in neurosteroid concentrations mediated by activation of the HPA axis may both contribute to the early acquisition phase of nicotine or morphine addiction and serve to counteract the anxiety-like behavior associated with nicotine or morphine withdrawal. However, the evidence that nicotine withdrawal did not increase neurosteroids, unless precipitated by mecamylamine, suggests that the role of these neurosteroids in spontaneous nicotine withdrawal may not be clear.

Plasma concentrations of anxiolytic neuroactive steroids in men with panic disorder.

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.

Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus.

An interaction with the GABA type A (GABA(A)) receptor has long been recognized as one of the main neurochemical mechanisms underlying many of the pharmacological actions of ethanol. However, more recent data have suggested that certain behavioral and electrophysiological actions of ethanol are mediated by an increase in brain concentration of neuroactive steroids that results from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Neuroactive steroids such as 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) are, in fact, potent and efficacious endogenous positive modulators of GABA(A) receptor function. Because neurosteroids can be synthesized de novo in the brain, we have investigated whether ethanol might affect both neurosteroid synthesis and GABA(A) receptor function in isolated rat hippocampal tissue. Here, we show that ethanol increases the concentration of 3alpha,5alpha-THP as well as the amplitude of GABA(A) receptor-mediated IPSCs recorded from CA1 pyramidal neurons in isolated hippocampal slices. These effects are shared by the neurosteroid precursor progesterone, the peripheral benzodiazepine receptor-selective agonist CB34, and gamma-hydroxybutyrate, all of which are known to increase the formation of neuroactive steroids in plasma and in the brain. The action of ethanol on GABA(A) receptor-mediated IPSC amplitude is biphasic, consisting of a rapid, direct effect on GABA(A) receptor activity and an indirect effect that appears to be mediated by neurosteroid synthesis. Furthermore, ethanol affects GABA(A) receptor activity through a presynaptic action, an effect that is not dependent on neurosteroid formation. These observations suggest that ethanol may modulate GABA(A) receptor function through an increase in de novo neurosteroid synthesis in the brain that is independent of the HPA axis. This novel mechanism may have a crucial role in mediating specific central effects of ethanol.

Plasma concentrations of anxiolytic neurosteroids in men with normal anxiety scores: a correlation analysis.

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.

Social isolation increases the response of peripheral benzodiazepine receptors in the rat.

Social isolation of rats for 30 days immediately after weaning reduces the cerebrocortical and plasma concentrations of progesterone, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG), and 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-TH DOC). The percentage increases in the brain and plasma concentrations of these neuroactive steroids apparent 30 min after intraperitoneal injection of the peripheral benzodiazepine receptor (PBR) ligand CB 34 (25 mg/kg) have now been shown to be markedly greater in isolated rats than in group-housed controls. The CB 34-induced increase in the abundance of 3alpha,5alpha-TH PROG was more pronounced in the brain than in the plasma of isolated rats. Analysis of [3H]PK 11195 binding to membranes prepared from the cerebral cortex, adrenals, or testis revealed no significant difference in either the maximal number of binding sites for this PBR ligand or its dissociation constant between isolated and group-housed animals. Social isolation also induced a small but significant decrease in the plasma concentration of adrenocorticotropic hormone. Moreover, CB 34 increased the plasma concentration of this hormone to a greater extent in isolated rats than in group-housed animals. The persistent decrease in the concentrations of neuroactive steroids induced by social isolation might thus be due to an adaptive decrease in the activity either of the hypothalamic-pituitary-adrenal axis or of PBRs during the prolonged stress, reflecting a defense mechanism to limit glucocorticoid production. The larger increase in neuroactive steroid concentrations induced by CB 34 and the enhanced pituitary response to this compound in isolated rats indicate that this mild stressor increases the response of PBRs.

Psychological effect of the oral contraceptive formulation containing 3 mg of drospirenone plus 30 microg of ethinyl estradiol.

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.