Cranial conjoined twins: surgical and anesthetic challenges for a routine procedure: adenoidectomy and examination of ears.

Craniopagus conjoined twins have long been the subject of interest because of the rarity and peculiarity of their juxtaposition. We present the surgical, airway and anesthetic challenges in craniopagus conjoined twins, in which one of the twins underwent adenoidectomy for obstructive sleep breathing disorder. The surgical procedure required a special setting from an anesthetic perspective whereby both children needed anesthesia due to the complex physiology of their brains and cardiovascular systems. As well, we took the opportunity to do bilateral ear examinations of both twins.

Safety and efficacy of continuous morphine infusions following pediatric cranial surgery in a surgical ward setting.

PURPOSE: Morphine is avoided by many neurosurgeons following cranial surgery. There exists a concern regarding the potential complications and a perception that cranial surgery is less painful than other surgical procedures. At British Columbia Children's Hospital continuous morphine infusions (CMI) have been used to control pain in pediatric neurosurgical patients. The purpose of this study was to compare the safety and efficacy of continuous intravenous morphine infusion to standard oral analgesics in a neurosurgical ward setting. METHODS: A retrospective review of medical records for 71 children was completed. The patients underwent either cranial reconstruction (2002-2007) or craniotomies for intradural pathology (2005-2007) at British Columbia Children's Hospital. Outcome measures included pain control and adverse events. Comparison was made between patients receiving a CMI and patients receiving acetaminophen and codeine. RESULTS: Thirty-seven children received CMI on the ward (30 cranial reconstruction and 7 craniotomy), while 34 (10 cranial reconstruction and 24 craniotomy) received acetaminophen and codeine. There was no statistical difference in pain control. There was significantly more nausea on post-operative day one in the CMI group (p = 0.002). There were no other significant adverse events. CONCLUSIONS: These findings suggest that CMI is comparable to acetaminophen and codeine with respect to analgesia and serious side effects. We recommend the use of CMIs as an alternative when pain is poorly controlled in post-operative pediatric neurosurgical patients to prevent the potential adverse consequences of inadequate analgesia.

Neuroactive steroid stereospecificity of ethanol-like discriminative stimulus effects in monkeys.

Positive modulation of GABA(A) and antagonism of N-methyl-D-aspartate receptors mediate the discriminative stimulus effects of ethanol. Endogenous neuroactive steroids produce effects similar to ethanol, suggesting that these steroids may modulate ethanol addiction. The four isomers of the functional esters at C-3 of the 3-hydroxy metabolites of 4-pregnene-3,20-dione (progesterone) [allopregnanolone (3alpha,5alpha-P), pregnanolone (3alpha,5beta-P), epiallopregnanolone (3beta,5alpha-P), and epipregnanolone (3beta,5beta-P)], a synthetic analog of steroids modified by endogenous sulfation [pregnanolone hemisuccinate (3alpha,5beta-P HS)], and a structurally similar, adrenally derived steroid [3alpha-hydroxy-5-androstan-17-one (3alpha,5alpha-A, androsterone)] were assessed for ethanol-like discriminative stimulus effects at 30 or 60 min after administration in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) with a 30-min pretreatment interval. The 3alpha-hydroxysteroids completely substituted for ethanol (80% of cases), whereas the 3beta-hydroxysteroids and 3alpha,5beta-P HS rarely substituted for ethanol (6% of cases). There were no sex differences. Compared with monkeys trained to discriminate 2.0 g/kg ethanol, 3alpha,5beta-P and 3alpha,5alpha-A substituted more potently in monkeys trained to discriminate 1.0 g/kg ethanol. Compared with the 5beta-reduced isomer (3alpha,5beta-P), the 5alpha isomer of pregnanolone (3alpha,5alpha-P) substituted for ethanol with 3 to 40-fold greater potency but was least efficacious in female monkeys trained to discriminate 2.0 g/kg ethanol. The data suggest that the discriminative stimulus effects of lower doses (1.0 g/kg) of ethanol are mediated to a greater extent by 3alpha,5beta-P- and 3alpha,5alpha-A-sensitive receptors compared with higher doses (2.0 g/kg). Furthermore, the discriminative stimulus effects of ethanol appear to be mediated by activity at binding sites that are particularly sensitive to 3alpha,5alpha-P.

[A Jehovah's Witness child with hemophilia B and factor IX inhibitors undergoing scoliosis surgery].

PURPOSE: To describe the successful perioperative hemostatic management of a Jehovah's Witness patient with hemophilia B and anaphylactic inhibitors to factor IX, undergoing scoliosis surgery. CLINICAL FEATURES: A 14 (1/2)-yr-old boy with severe hemophilia B who had a history of anaphylactic inhibitors to factor IX was scheduled to undergo corrective scoliosis surgery. He was initially started on epoetin alfa and iron supplementation to maximize preoperative red cell mass. Additionally, he was placed on a desensitization protocol of recombinant coagulation factor IX (rFIX) and was then treated with activated recombinant coagulation factor VII (rFVIIa) during the postoperative period. Tranexamic acid was given concomitantly. The intraoperative blood loss was approximately 350 mL. The nadir hemoglobin concentration was 111 g.L(-1) on postoperative days one and two. On postoperative day 11, the patient was stable and discharged home with a hemoglobin of 138 g.L(-1). He did not require blood transfusion and no adverse events were observed. CONCLUSIONS: The use of rFIX, rFVIIa, erythropoetin, iron, and tranexamic acid before, during and after scoliosis surgery may be a viable and safe option for hemophilia patients with inhibitors, who refuse blood products.

Allopregnanolone decrease with symptom improvement during placebo and gonadotropin-releasing hormone agonist treatment in women with severe premenstrual syndrome.

BACKGROUND: Neurosteroids such as allopregnanolone and pregnanolone are suggested to be of importance for the pathophysiology of premenstrual dysphoric disorder. The aim of this study was to investigate whether the luteal-phase serum concentrations of these neurosteroids are associated with improvement of premenstrual symptoms in 12 women with severe premenstrual syndrome after treatment with low-dose gonadotropin-releasing hormone agonist and placebo. METHODS: Daily ratings for mood and physical symptoms were made prior to treatment and throughout the study. Serum progesterone, allopregnanolone and pregnanolone were assessed in the luteal phase (cycle day -9 to cycle day -1). Based on their symptom ratings, subjects were grouped as either buserelin responders (n = 6) or placebo responders (n = 6). RESULTS: Buserelin responders displayed decreased levels of allopregnanolone (p < 0.05) and progesterone (p < 0.05) in parallel with improvement of symptoms. During the placebo treatment, the placebo responders had lower serum allopregnanolone concentrations than buserelin responders (p < 0.05). This was associated with improvement in symptoms compared with pre-treatment ratings. CONCLUSION: Treatment response, whether induced by buserelin or placebo, appears to be associated with a decrease in allopregnanolone concentration.

Steroid pregnenolone sulfate enhances NMDA-receptor-independent long-term potentiation at hippocampal CA1 synapses: role for L-type calcium channels and sigma-receptors.

Severe stress elevates plasma and CNS levels of endogenous neuroactive steroids that can contribute to the influence of stress on memory formation. Among the neuroactive steroids, pregnenolone sulfate (PREGS) reportedly strengthens memories and is readily available as a memory-enhancing supplement. PREGS actions on memory may reflect its ability to produce changes in memory-related neuronal circuits, such as long-term potentiation (LTP) of excitatory transmission in hippocampus. Here, we report a previously undiscovered pathway by which PREGS exposure promotes activity-dependent LTP of field excitatory postsynaptic potentials at CA1 synapses in hippocampal slices. Thus, application of PREGS, but not the phosphated conjugate of the steroid, selectively facilitates the induction of a slow-developing LTP in response to high-frequency (100 Hz) afferent stimulation, which is not induced in the absence of the steroid. The slow-developing LTP is independent of NMDA-receptor function (i.e., dAP5 insensitive) but dependent on functional L-type voltage-gated calcium channels (VGCC) and sigma-receptors. By contrast, PREGS at the highest concentration tested produces a depression in NMDA-receptor-dependent LTP, which is evident when sigma-receptor function is compromised by the presence of a sigma-receptor antagonist. We found that at early times during the induction phase of L-type VGCC-dependent LTP, PREGS via sigma-receptors transiently enhances presynaptic function. As well, during the maintenance phase of L-type VGCC-dependent LTP, PREGS promotes a further increase in presynaptic function downstream of LTP induction, as evidenced by a decrease in paired-pulse facilitation. The identification of complex regulatory actions of PREGS on LTP, involving sigma-receptors, L-type VGCCs, NMDA-receptors, and inhibitory circuits will aid future research endeavors aimed at understanding the precise mechanisms by which this stress-associated steroid may engage multiple LTP-signaling pathways that alter synaptic transmission at memory-related synapses.

Pharmacokinetic and behavioral effects of allopregnanolone in healthy women.

RATIONALE: The behavioral effects of allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) in women are not known. OBJECTIVE: Allopregnanolone, a neuroactive steroid secreted by the mammalian ovary, exerts its anesthetic, anxiolytic, and sedative/hypnotic effects through potentiation of GABAA receptors. The purpose of this study was to evaluate the behavioral effects of allopregnanolone in healthy women. METHODS: Ten healthy women were given three increasing intravenous doses of allopregnanolone in the follicular phase of the menstrual cycle. Saccadic eye movement parameters and visual analogue scales of sedation were used to evaluate the behavioral response of allopregnanolone. Repeated blood samples for analyses of allopregnanolone were drawn throughout the study day. RESULTS: Exogenously administered allopregnanolone decreases saccadic eye movement parameters and increases subjective ratings of sedation that correlate with increased serum concentrations of this neuroactive steroid. CONCLUSION: The behavioral effects of allopregnanolone are similar to that of its 5beta-stereoisomer, pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one). Apart from fatigue and mild nausea, allopregnanolone given in a cumulative dose of 0.09 mg/kg did not have any adverse effects.

3alpha-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period.

Allopregnanolone (ALLO) and pregnanolone (PREG), the 3alpha-reduced metabolites of progesterone (PROG), are potent modulators of gamma-aminobutyric acid type A receptors that may function as endogenous anxiolytics. They are purported to be involved in the etiology or expression of clinical depression. In the present study we quantified ALLO and PREG, as well as PROG, 5alpha-dihydroprogesterone (5alpha-DHP), 5beta-dihydroprogesterone (5beta-DHP), epiallopregnanolone and pregnenolone (PREGNEN), in plasma from healthy women at five time points during pregnancy and the postpartum period. Analysis was by gas chromatography/electron capture - negative chemical ionization - mass spectrometry. Neuroactive steroids increased significantly from 10 to 36 weeks of pregnancy, except for 5beta-DHP and PREGNEN which did not change significantly. PROG was the most abundant steroid throughout pregnancy, followed by 5alpha-DHP and ALLO. Metabolite to precursor ratios differed depending on the enzyme and substrate: the turnover of PROG to 5alpha-DHP (catalyzed by 5alpha-reductase) was stable while the conversion of PROG to 5beta-DHP (catalyzed by 5beta-reductase) decreased later in pregnancy. 3alpha-Hydroxysteroid oxidoreductase-mediated turnover of 5alpha- and 5beta-DHP to their metabolites ALLO and PREG, respectively, rose during pregnancy, but the turnover of 5alpha-DHP to ALLO dropped at the late prenatal visit. At 6 weeks postpartum all steroids were significantly reduced compared with late prenatal values, with 5alpha-DHP being the most abundant postpartum steroid. These results provide the basis for further study of neuroactive steroids in psychiatric conditions of pregnancy and the postpartum period.

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.

Endogenous gamma-aminobutyric acid (GABA)(A) receptor active neurosteroids and the sedative/hypnotic action of gamma-hydroxybutyric acid (GHB): a study in GHB-S (sensitive) and GHB-R (resistant) rat lines.

In the rat brain, gamma-hydroxybutyric-acid (GHB) increases the concentrations of 3alpha-hydroxy,5alpha-pregnan-20-one (allopregnanolone, 3alpha,5alpha-THP) and 3alpha,21-dihydroxy,5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone/3alpha,5alphaTHDOC), two neurosteroids acting as positive allosteric modulators of gamma-aminobutyric acid (GABA)(A) receptors. This study was aimed at assessing whether neurosteroids play a role in GHB-induced loss of righting reflex (LORR). Basal and GHB-stimulated brain concentrations of endogenous 3alpha,5alpha-THP and 3alpha,5alpha-THDOC were analyzed in two rat lines, GHB-sensitive (GHB-S) and GHB-resistant (GHB-R), selectively bred for opposite sensitivity to GHB-induced sedation/hypnosis. Basal neurosteroid concentrations were similar in brain cortex of the two rat lines. However, in male GHB-S rats, administration of GHB (1000 mg/kg, i.p., 30 min) increased brain cortical concentrations of 3alpha,5alpha-THP and 3alpha,5alpha-THDOC 7- and 2.5-fold, respectively, whilst male GHB-R animals displayed only a 4- and 2-fold increase, respectively. In GHB-S rats this increase lasted up to 90 min and declined 180 min following GHB administration, a time course that matches LORR onset and duration. In contrast, in GHB-R rats, which failed to show GHB-induced LORR, brain cortical 3alpha,5alpha-THP and 3alpha,5alpha-THDOC had returned to control values within 90 min. At onset of LORR, a similar increase in brain cortical levels of 3alpha,5alpha-THP and 3alpha,5alpha-THDOC (2-3-fold) was observed in GHB-S female rats and in the few female GHB-R rats that lost the righting reflex after GHB administration, but not in female GHB-R rats failing to show LORR. Sub-hypnotic doses (7.5 and 12.5 mg/kg, i.p.) of pregnanolone, administered 10 min before GHB, dose-dependently facilitated the expression of GHB-induced LORR in GHB-R male rats. These results suggest that the GHB-induced increases of brain 3alpha,5alpha-THP and 3alpha,5alpha-THDOC concentrations are implicated in the eliciting of the sedative/hypnotic action of GHB.

Characterization of the discriminative stimulus effects of the neuroactive steroid pregnanolone in DBA/2J and C57BL/6J inbred mice.

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABA(A). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. This study aimed to examine the effects of strain and sex on the discriminative stimulus effects of pregnanolone. Twelve male and female DBA/2J mice and 12 male and female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone from saline. The male C57BL/6J mice had to be removed from the study due to increased seizures apparently associated with the chronic intermittent pregnanolone administration used in drug discrimination. GABA(A)-positive modulators, neuroactive steroids, N-methyl-d-aspartate (NMDA) antagonists, and 5-hydroxytryptamine (5-HT)(3) agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice, a benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for the stimulus effects of pregnanolone. NMDA antagonists, 5-HT(3) agonists, and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either sex or strain. Pentobarbital and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. Differences in sensitivities to neurosteroids between the two strains were not evident. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest that many of the previously documented neurosteroid-induced behavioral differences between the DBA/2J and C57BL/6J are acute effects and are not apparent in a drug discrimination procedure.

Electrophysiological effects of allopregnanolone in rats with a history of ethanol exposure.

BACKGROUND: Sensitivity to the anticonvulsant effects of allopregnanolone (ALLO) is enhanced during the early phase of ethanol (EtOH) withdrawal. However, it is unclear whether this enhanced sensitivity generalizes to ALLO's neurobehavioral effects during protracted abstinence. The purpose of this study was to examine the neurophysiological effects of ALLO in rats with a history of chronic EtOH exposure after a protracted period of abstinence. METHODS: Male Wistar rats were exposed to EtOH vapor for 14 hr/day for 5 weeks. Blood EtOH levels were maintained between 200 and 250 mg/dl. The effects of ALLO (0.0-10 mg/kg, intraperitoneally) on motor activity, the electroencephalogram (EEG), and auditory event-related potentials then were assessed after 6 to 8 weeks of abstinence from EtOH. RESULTS: ALLO's effects on the EEG were consistent with previous studies and were unaffected by EtOH exposure. ALLO increased high-frequency EEG power and shifted peak EEG frequencies in a benzodiazepine- and barbiturate-like manner in both the cortex and the hippocampus. The effects of ALLO on event-related potentials were attenuated in rats with a history of EtOH exposure. Low doses of ALLO (1 and 5 mg/kg) reduced cortical P1 amplitude in response to the standard tone but only in the control group. ALLO also increased N1 amplitude in the hippocampus of the control group while having no significant effect in EtOH-exposed rats. Low doses of ALLO (1 and 5 mg/kg) were found to increase motor activity. CONCLUSIONS: These data indicate that a history of EtOH exposure attenuates some of the neurophysiological effects of ALLO in a manner consistent with cross-tolerance. Taken together, these data suggest that increased sensitivity to ALLO's neurobehavioral effects is limited to the early phases of EtOH withdrawal and may not extend to more protracted periods of abstinence.

Discriminative stimulus effects of 5.6 mg/kg pregnanolone in DBA/2J and C57BL/6J inbred mice.

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as gamma-aminobutyric acid(A) (GABA(A)). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. A previous study examining the discriminative stimulus effects of 10 mg/kg pregnanolone in DBA/2J and C57BL/6J mice showed pregnanolone's discriminative stimulus to be mediated primarily through GABA(A) positive modulation. This study examined the discriminative stimulus effects of a lower training dose (5.6 mg/kg) of pregnanolone in DBA/2J and C57BL/5J mice. Twelve male DBA/2J mice and 12 male C57BL/6J mice were trained to discriminate 5.6 mg/kg pregnanolone. GABA(A)-receptor positive modulators, neuroactive steroids, NMDA receptor antagonists, and 5-HT(3) receptor agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for pregnanolone. In the DBA/2J mice, NMDA receptor antagonists showed generalization to the discriminative stimulus cues of pregnanolone, an effect not seen in the C57BL/6J mice. 5-HT(3) receptor agonists and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either strain. AlloTHDOC and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest GABA(A)-receptor positive modulation as the predominant receptor mechanism mediating the discriminative stimulus effects of pregnanolone. NMDA receptor antagonism was suggested in the DBA/2J mice and may represent a heterogenous cue produced by the lower training dose of pregnanolone.

Fetal alcohol exposure alters neurosteroid levels in the developing rat brain.

Neurosteroids are modulators of neuronal function that may play important roles in brain maturation. We determined whether chronic prenatal ethanol exposure altered neurosteroid levels in the developing brain. Rat dams were exposed to: (i) a 5% ethanol-containing liquid diet that produces peak maternal blood alcohol levels near the legal intoxication limit (approximately 0.08 g/dL); (ii) an isocaloric liquid diet containing maltose-dextrin instead of ethanol with pair-feeding; (iii) rat chow ad libitum. Neurosteroid levels were assessed in offspring brains using radioimmunoassay or gas chromatography-mass spectrometry techniques. A prenatal ethanol exposure-induced increase in pregnenolone sulfate levels, but not dehydroepiandrosterone sulfate levels, was evident at the earliest time point studied (embryonic day 14). This effect lasted until post-natal day 5. Levels of other neurosteroids were assessed at embryonic day 20; pregnenolone levels, but not allopregnanolone levels, were elevated. Pregnenolone sulfate levels were not altered in the maternal brain. Neither pregnenolone nor pregnenolone sulfate levels were significantly altered in the fetal liver, placenta and maternal blood, indicating that the effect of ethanol is not secondary to accumulation of peripherally-produced steroids. Fetal ethanol exposure has been shown to decrease both cellular and behavioral responsiveness to neurosteroids, and our findings provide a plausible explanation for this effect.

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.

Failure of gamma-hydroxybutyric acid both to increase neuroactive steroid concentrations in adrenalectomized-orchiectomized rats and to induce tolerance to its steroidogenic effect in intact animals.

Gamma-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.

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.