Pharmacology of endogenous neuroactive steroids

Neuroactive steroids are potent endogenous neuromodulators with rapid actions in the central nervous system. Neuroactive steroids have been claimed to have specific physiological roles in normal or pathological brain function. This article reviews the emerging evidence that progesterone-, deoxycorticosterone-, and testosterone-derived endogenous neuroactive steroids play an important role in the modulation of neural excitability and brain function. Neuroactive steroids such as allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC) are extremely potent positive allosteric modulators of GABAA receptors with sedative, anxiolytic, and anticonvulsant properties.The sulfated neuroactive steroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), which are negative GABAA receptor modulators, induce anxiogenic and proconvulsant effects. Thus, natural fluctuations in neuroactive steroid levels during the menstrual cycle and stress could affect several nervous system functions. There is strong evidence that allopregnanolone and THDOC are involved in the pathophysiology of premenstrual syndrome, catamenial epilepsy, major depression, and stress-sensitive brain disorders. Neuroactive steroids PS and DHEAS have been shown to modulate memory functions. However, the significance of the testosterone-derived neuroactive steroid 3alpha-androstanediol is not well understood. Like naturally occurring neuroactive steroids, synthetic derivatives such as ganaxolone have been proven in preclinical and clinical studies to be effective anticonvulsants with great potential for human use. Future research on inhibition or stimulation of specific neuroactive steroid synthesizing enzymes could provide an improved understanding and novel approaches for the treatment of anxiety, epilepsy, and depression.     

Neuroactive steroids as modulators of depression and anxiety

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3alpha-reduced pregnane steroids are potent positive allosteric modulators of the GABA type A-receptor. During major depression there is a dysequilibrium of 3alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment we studied the impact of non-pharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroids observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder changes in neuroactive steroid composition have been observed opposite of those seen in depression. These changes may represent counterregulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimental panic induction with either cholecystokinin-tetrapeptide or sodium lactate there was a pronounced decline in the concentrations of 3alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3alpha, 5alpha-tetrahydrodeoxycorticosterone, allotetrahydrodeoxycorticosterone. The modulation of GABA type A-receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds.     

Physiological role of adrenal deoxycorticosterone-derived neuroactive steroids in stress-sensitive conditions

Stress increases plasma and brain concentrations of corticosteroids and neuroactive steroids. Cortisol is the most important stress hormone in the hypothalamic pituitary adrenocortical system. However, significant amounts of the mineralocorticoid deoxycorticosterone are also released during stress. Deoxycorticosterone undergoes biotransformation to allotetrahydrodeoxycorticosterone, a neuroactive steroid with anxiolytic and anticonvulsant properties. Our studies indicate that the anticonvulsant activity of deoxycorticosterone is mediated by its conversion to allotetrahydrodeoxycorticosterone, which is a potent positive allosteric modulator of GABA(A) receptors. Although the role of allotetrahydrodeoxycorticosterone within the brain is undefined, recent studies indicate that stress induces increases in allotetrahydrodeoxycorticosterone to levels that can activate GABA(A) receptors. These results might have significant implications for human stress-sensitive conditions such as epilepsy, panic disorder, post-traumatic stress disorder, and major depression. In epilepsy, a role for adrenal allotetrahydrodeoxycorticosterone in seizure susceptibility has been suggested. Recent preclinical studies indicate a role of neuroactive steroids in ethanol actions. Although these studies provide a better understanding of the role of allotetrahydrodeoxycorticosterone and related neuroactive steroids in acute stress, further studies are clearly warranted to ascertain the specific role of neuroactive steroids in the pathophysiology of chronic stress and related brain conditions.     

Neuroactive steroid regulation of neurotransmitter release in the CNS: Action, mechanism and possible significance

Neuroactive steroids refer to steroids that are capable of regulating neuronal activities. Neuroactive steroids, synthesized either de novo in the nervous tissue or in the peripheral endocrine glands or as synthetic steroids, have exhibited numerous important modulatory effects on brain functions and brain diseases. At the cellular level, in addition to the effect on postsynaptic receptors, most neuroactive steroids, including pregnenolone, pregnenolone sulfate, progesterone, allopregnanolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone and estradiol, have modulatory effects on the release of multiple neurotransmitters like glutamate, GABA, acetylcholine, norepinephrine, dopamine and 5-HT. Many of these effects occur in the brain regions involved in learning and memory, emotion, motivation, motor and cognition. Moreover, the effects are rather complicated, maybe depending on many factors such as types of neuroactive steroids, brain regions and presynaptic functional states. The mechanisms are also complicated. Many of them involve rapid non-genomic effects on presynaptic receptors and ion channels like sigma-1 receptor, α₁ receptor, nicotine receptor, D1 receptor, NMDA receptor, GABA_A receptor and L-type Ca²⁺ channels. These effects have made neuroactive steroids important regulators of synaptic transmission in the central nervous system and constitute the major basis for many important actions of neuroactive steroids on brain functions and brain diseases.     

Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia

BACKGROUND: Animal studies have shown that neuroactive steroids modulate the activity of the gamma-aminobutyric acid type A/benzodiazepine receptor complex and that these steroids display anxiolytic or anxiogenic activity depending on their positive (e.g. allopregnanolone) or negative allosteric modulation (e.g. dehydroepiandrosterone sulphate) of this receptor. This study compared plasma levels of allopregnanolone, dehydroepiandrosterone sulphate and pregnenolone sulphate in healthy controls and in patients with generalized social phobia, as assessed with the Mini-International Neuropsychiatric Interview. METHODS: Plasma concentrations of allopregnanolone, pregnenolone sulphate, and dehydroepiandrosterone sulphate were measured in 12 unmedicated male patients with generalized social phobia and 12 matched healthy male volunteers. RESULTS: Concentrations of pregnenolone sulphate were significantly lower in patients with generalized social phobia than in healthy controls. No statistically significant differences were found for the concentrations of allopregnanolone and dehydroepiandrosterone sulphate in plasma. CONCLUSIONS: These results are particularly interesting since we also observed lower pregnenolone sulphate concentrations in male patients suffering from generalized anxiety disorder. Their relevance to the pathophysiology of social anxiety disorder remains to be determined.     

Plasma levels of neuroactive steroids are increased in untreated women with anorexia nervosa or bulimia nervosa

OBJECTIVE: Animal data suggest that neuroactive steroids, such as 3alpha,5alpha-tetrahydroprogesterone (3a,5a-THP), dehydroepiandrosterone (DHEA), and its sulfated metabolite (DHEA-S), are involved in the modulation of eating behavior, aggressiveness, mood, and anxiety. Anorexia nervosa (AN) and bulimia nervosa (BN) are eating disorders characterized by abnormal eating patterns, depressive and anxious symptoms, enhanced aggressiveness, and endocrine alterations. Previous studies reported decreased blood levels of DHEA and DHEA-S in small samples of anorexic patients, whereas no study has been performed to evaluate the secretion of these neuroactive steroids in BN as well as the production of 3alpha,5alpha-THP in both AN and BN. Therefore, we measured plasma levels of DHEA, DHEA-S, 3alpha,5alpha-THP and other hormones in patients with AN or BN and explored possible relationships between neuroactive steroids and psychopathology. METHOD: Ninety-two women participated in the study. There were 30 drug-free AN patients, 32 drug-free BN patients, and 30 age-matched, healthy control subjects. Blood samples were collected in the morning for determination of hormone levels. Eating-related psychopathology, depressive symptoms, and aggressiveness were rated by using specific psychopathological scales. RESULTS: Compared with healthy women, both AN and BN patients exhibited increased plasma levels of 3alpha,5alpha-THP, DHEA, DHEA-S, and cortisol but reduced concentrations of 17beta-estradiol. Plasma testosterone levels were decreased in anorexic women but not in bulimic women. Plasma levels of neuroactive steroids were not correlated with any clinical or demographic variable. CONCLUSIONS: These findings demonstrate increased morning plasma levels of peripheral neuroactive steroids in anorexic and bulimic patients. The relevance of such hormonal alterations to the pathophysiology of eating disorders remains to be elucidated.     

Low doses of ethanol and a neuroactive steroid positively interact to modulate rat GABAA receptor function

Fast inhibitory responses in the central nervous system are mediated by the GABA_A receptor. The activation and function of the GABA_A receptor can be modulated by a variety of compounds including benzodiazepines, barbiturates and neuroactive steroids. Modulation of the GABA_A receptor function by ethanol has been observed in some but not all studies. We have studied the effect of ethanol at concentrations corresponding to light intoxication on the function of the recombinant GABA_A receptor containing α1β2γ2 subunits. The experiments were performed both in the absence and presence of low, subthreshold concentrations of a neuroactive steroid. The results demonstrate that, in the presence of the steroid, 0.05 % (9 m m ) ethanol potentiates the GABA_A receptor function by increasing the channel mean open duration. No effect was observed on the channel closed time durations. The data suggest that ethanol influences channel closing with no effect on the affinity of the receptor for GABA or the channel opening rate constant.     

Olanzapine counteracts stress-induced anxiety-like behavior in rats

Atypical antipsychotics, such as olanzapine, have been reported to display anxiolytic properties as shown in several preclinical and clinical studies. Furthermore, several experimental evidences have shown that olanzapine reduces fear and anxiety in activated anxiety-like behavior test such as Geller-Seifter test, ultrasonic vocalization test and stress-induced EtOH consumption. Here, we hypothesized that the anxiolytic action of olanzapine might be due to via an indirect activation of the γ-amino butyric acid (GABA)-ergic system through 3α-hydroxy-5α-pregnan-20-one [allopregnanolone (ALLO)], a potent neuroactive steroid that positively modulates the benzodiazepine-γ-aminobutyric acid type A (GABA_A)/benzodiazepine receptors complex. To address this question, we used a preclinical animal test to screen for novel anxiolytic compounds – the elevated plus-maze (EPM) – in basal condition and after 45 min restrain stress after acute or repeated (21 days) administration of olanzapine (0.5 mg/kg, i.p.). In this condition, we therefore study the effect of the 5-alpha-reductase inhibitor finasteride (FIN) (50 mg/kg) after co-administration with olanzapine. FIN is an inhibitor of steroidogenic enzymes which acts by inhibiting type II 5-alpha reductase, the enzyme that converts into 5-alpha-reduced metabolites like the GABA_A positive neuroactive steroid ALLO. Results showed an anxiolytic effect of the acute, but not of the chronic, treatment with olanzapine only in stressed rats. This anxiolytic effect was counteracted by the co-administration with FIN. These evidences suggest that the anxiolytic effects of olanzapine might be due to possible action of olanzapine on steroid function via activation of GABA system.     

Neuroprotective effects of a ligand of translocator protein-18kDa (Ro5-4864) in experimental diabetic neuropathy

Peripheral neuropathy represents an important complication of diabetes involving a spectrum of structural, functional and biochemical alterations in peripheral nerves. Recent observations obtained in our laboratory have shown that the levels of neuroactive steroids present in the sciatic nerve of rat raised diabetic by a single injection of streptozotocin (STZ) are reduced and that, in the same experimental model, treatment with neuroactive steroids, such as progesterone, testosterone and their derivatives show neuroprotective effects. On this basis, an interesting therapeutic strategy could be to increase the levels of neuroactive steroids directly in the nervous system. With this perspective, ligands of translocator protein-18 kDa (TSPO) may represent an interesting option. TSPO is mainly present in the mitochondrial outer membrane, where it promotes the translocation of cholesterol to the inner mitochondrial membrane, and, as demonstrated in other cellular systems, it allows the transformation of cholesterol into pregnenolone and the increase of steroid levels. In the diabetic model of STZ rat, we have here assessed whether treatment with Ro5-4864 (i.e., a ligand of TSPO) could increase the low levels of neuroactive steroids in sciatic nerve and consequently to be protective in this experimental model. Data obtained by liquid chromatography–tandem mass spectrometry show that treatment with Ro5-4864 was able to significantly stimulate the low levels of pregnenolone, progesterone and dihydrotestosterone observed in the sciatic nerves of diabetic rats. The treatment with Ro5-4864 also counteracted the impairment of NCV and thermal threshold, restored skin innervation density and P0 mRNA levels, and improved Na⁺,K⁺-ATPase activity. In conclusion, data here reported show for the first time that a TSPO ligand, such as Ro5-4864, is effective in reducing the severity of diabetic neuropathy through a local increase of neuroactive steroid levels.     

The membrane interaction of drugs as one of mechanisms for their enantioselective effects

The discrimination between different enantiomers of chiral compounds by the biological system is medically important as the pharmacological and toxicological effects of enantiomeric drugs significantly differ depending on their stereostructures. One enantiomer is preferred over its enantiomeric counterpart and a racemic mixture for higher activity or lower toxicity. Such enantioselectivity has been exclusively explained by the stereostructure-specific interactions with receptors, channels and enzymes of drugs including general and local anesthetics, sedatives, hypnotics, anti-inflammatory drugs, analgesics and β-adrenergic antagonists. These drugs can act on not only protein targets but also lipid biomembranes. Almost all of the relevant proteins are embedded in or associated with membrane lipid bilayers. Therefore, we propose one of possible mechanisms that drugs might enantioselectively interact with membrane lipids and induce changes in membrane property like fluidity which are discriminable between enantiomers. If the induced changes are different between enantiomers, enantiomeric drugs would differently influence the membrane lipid environments for receptors, channels and enzymes, resulting in the enantioselectivity of drug effects. The enantioselective membrane interactions of drugs could be mediated by membrane component cholesterol and phospholipids, both of which have chiral centers in structure as well as drug enantiomers. Chiral membrane lipids possibly exhibit the preference for the interactions with drug molecules of either the same chirality or the different chirality, producing the selectivity to one drug enantiomer. The proposed hypothesis may be available to investigate more useful medicines based on the novel concept of drug enantioselectivity.     

Neuroprotective effects of dihydroprogesterone and progesterone in an experimental model of nerve crush injury

A satisfactory management to ensure a full restoration of peripheral nerve after trauma is not yet available. Using an experimental protocol, in which crush injury was applied 1 cm above the bifurcation of the rat sciatic nerve for 20 s, we here demonstrate that the levels of neuroactive steroids, such as pregnenolone and progesterone (P) metabolites (i.e. dihydroprogesterone, DHP, and tetrahydroprogesterone, THP) present in injured sciatic nerve were significantly decreased. On this basis, we have focused our attention on DHP and its direct precursor, P, analyzing whether these two neuroactive steroids may have neuroprotective effects on biochemical, functional and morphological alterations occurring during crush-induced degeneration-regeneration. We demonstrate that DHP and/or P counteract biochemical alterations (i.e. myelin proteins and Na(+),K(+)-ATPase pump) and stimulate reelin gene expression. These two neuroactive steroids also counteract nociception impairment, and DHP treatment significantly decreases the up-regulation of myelinated fibers' density occurring in crushed animals. Altogether, these observations suggest that DHP and P (i.e. two neuroactive steroids interacting with progesterone receptor) may be considered protective agents in case of nerve crush injury.     

Antinociceptive effects of the neuroactive steroid, 3alpha-hydroxy-5alpha-pregnan-20-one and progesterone in the land snail, Cepaea nemoralis

Results of investigations with vertebrates have implicated neuroactive steroids and in particular 5alpha-reduced metabolites of progesterone such as 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP/3A5P and originally allopregnanolone) in the rapid modulation of diverse functions including that of nociceptive sensitivity. These effects have been indicated to involve modulation of GABA receptors. Results of recent phylogenetic studies have revealed the presence of GABA receptors in invertebrates that may also be subject to modulation by steroids and neuroactive steroids. The present study examined the effects of the neuroactive steroid, 3alpha-hydroxy-5alpha-pregnan-20-one, as well as progesterone on aversive thermal (nociceptive) responses in a mollusc, the land snail, Cepaea nemoralis. 3alpha-Hydroxy-5alpha-pregnan-20-one had significant dose-related (0.01-1.0 microg) antinociceptive effects in Cepaea increasing the latency of response to a 40 degrees C surface, with maximum effects being evident 15-30 min after administration. These effects of 3alpha-hydroxy-5alpha-pregnan-20-one were stereospecific, with the stereoisomer 3beta-hydroxy-5alpha-pregnan-20-one (3B5P) failing to affect nociceptive responses. Progesterone also had significant dose-related (0.10-10 microg) antinociceptive effects that, however, were delayed in onset and relatively prolonged (60-120 min), suggestive of the formation of active metabolites. The presence of endogenous progesterone (12.36+/-0.17 ng/g tissue) was ascertained by a radioimmunoassay further supporting a functional role for steroids in Cepaea. The antinociceptive effects of 3alpha-hydroxy-5alpha-pregnan-20-one and progesterone were blocked by the GABA antagonists, bicuculline and picrotoxin, while being relatively insensitive to opioid and N-methyl-D-aspartate antagonists. These results suggest an early evolutionary development and phylogenetic continuity of neuroactive steroid and GABA involvement in the mediation of nociception.     

Progestogens and brain: An update

Each synthetic progestins has its own specific activities on different tissues, which can vary significantly between progestins of different classes and even within the same class. Indeed, different progestins may support or oppose the effects of estrogen depending on the tissue, thereby supporting the concept that the clinical selection of progestins for HRT is critical in determining potential positive or detrimental effects. These actions might be particularly relevant in the central nervous system (CNS) where progesterone (P) has pivotal roles besides reproduction and sexual behavior, going from neuropsychological effects to neuroprotective functions. Growing evidence supports the idea that synthetic progestins differ significantly in their brain effects, and clinical studies indicate that these differences also occur in women. Molecular and cellular characterization of the signaling properties of synthetic progestins in brain cells is therefore required and is hoped will lead to a better clinical utilization of the available compounds, as well as to new concepts in the engineering of new molecules. The aim of the present paper is to briefly review and compare neuroendocrine effects of progestogens with special reference to P metabolism into neuroactive steroids and the opioids system.     

Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis

One important complication of diabetes is damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Neuroactive steroids might be interesting since they have been recently identified as promising neuroprotective agents in several models of neurodegeneration. We have assessed whether chronic treatment with progesterone (P), dihydroprogesterone (DHP) or tetrahydroprogesterone (THP) had neuroprotective effects against streptozotocin (STZ)-induced diabetic neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Using gas chromatography coupled to mass-spectrometry, we found that three months of diabetes markedly lowered P plasma levels in male rats, and chronic treatment with P restored them, with protective effects on peripheral nerves. In the model of STZ-induced of diabetic neuropathy, chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na(+),K(+)-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22, suggesting that these neuroactive steroids, might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while the expression of myelin proteins and Na(+),K(+)-ATPase activity are only stimulated by P and DHP (i.e. two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber (IENF) density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoted to evaluating the role of PR and GABA-A receptor in these protective effects.     

Neuropharmacological effects of Nigerian honey in mice

Honey is a natural sweet substance that bees produce by transforming flower nectar or other sweet secretions of plants. It has widespread use in traditional medicine in various parts of the world. It has been reported to assist in building the entire central nervous system. The beneficial effects of honey have been attributed to the possible polyphenolic contents and some other constituents. The geographical locations and the sources of plant nectars may contribute to the effects of honey samples. Thus, we evaluated the neuropharmacological effects of six samples of honey (10%, 20% and 40%(V)/v, p.o.) from three geographical locations of Nigeria using the following behavioral models: Novelty-induced behaviors (NIB), learning and memory, pentobarbital-induced hypnosis, anxiolytic, anticonvulsant, analgesic and antidepressant models in mice. The results showed that honey significantly (p< 0.05) decreased locomotion and rearing behaviors in NIB and amphetamine-induced locomotor activity when compared to the control group. Exploratory behavior was significantly increased in both holeboard and elevated plus maze but had no significant effect on spatial working memory. Honey sample from Umudike has significant hypnotic and anticonvulsant effects. The antinociceptive models (hot plate and tail flick tests) showed that the honey samples significantly increased the pain reaction time and naloxone blocked these central antinociceptive effects. The force swimming test showed that only the Idanre (ID) honey sample had antidepressant effect. In conclusion, some of these honey samples have central inhibitory property, anxiolytic, antinociceptive, anticonvulsant and antidepressant effects, thus may be used as nutraceutic. It can also be inferred that some of these effects are probably mediated through dopaminergic and opioidergic systems.     

B-cells and their targeting in rheumatoid arthritis--current concepts and future perspectives

Rheumatoid arthritis (RA) is a chronic, autoimmune disease that affects primarily the joints and without proper treatment results in their progressive destruction. In addition to T-cells, B-cells play a central role in the pathogenesis of this disease. The synovial tissue is an active site of B-cell accumulation, plasma cell differentiation and in situ antibody-production in RA. As part of the complex role of B-cells in the joints and synovial membrane of RA patients, B cells secrete chemokines and cytokines and may function as antigen presenting cells. The multifaceted pathogenic function of B-cells identifies them as excellent targets for immunosuppressive therapy. B-cell targeting involves a wide spectrum of molecules, for example the B-cell antigen CD20 that allows specific and effective B-cell depletion. Another target, CD79, expressed by B-cell and plasma cell precursors is an obvious candidate that induces apoptosis as well as inhibition of B-cell receptor (BCR) activation and possibly depletion of ectopic germinal centers (GC). Inhibition of B-cell co-stimulatory molecules such as CD40, CD80/86 and ICOS, can lead to diminished B-cell activation. Moreover, anti-chemokine and anti-cytokine therapies can be efficacious in RA by the disruption of B-cell activation and autoantibody production, B-cell synovial migration and ectopic GC formation. Finally, targeting the signal transduction pathways required for proximal BCR signaling has also been found efficacious in early clinical trials in RA. Even so, some B cells inhibit immune responses, these regulatory B cells may play a part in immune regulation in patients and it is unclear what effects B cell depletion strategies have in terms of such B cell subsets. This review discusses current strategies of targeting B-cells as therapeutic candidates in the management of RA. Better insights into the pathogenic role of B-cells provide efficacious opportunities to improve both therapy and prognosis of patients with RA.     

Effects of the vasopressin (V1b) receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, on FG 7142-induced increase in acetylcholine and norepinephrine release in the rat

Arginine vasopressin and corticotropin-releasing factor are two neuroactive peptides that regulate hypothalamic-pituitary-axis and associated stress response. While the potential antidepressant and anxiolytic profiles of corticotropin-releasing factor 1 antagonists have been well studied, the concept of blockade of vasopressin system as another approach for the treatment of emotional processes has only been made available recently by the synthesis of the first non-peptide antagonist at the V1b receptor, SSR149415. In the present study SSR149415 has been compared with the corticotropin-releasing factor 1 antagonist SSR125543 and with anxiolytic and antidepressant drugs on the response of hippocampal cholinergic and cortical noradrenergic systems to the anxiogenic benzodiazepine receptor inverse agonist FG 7142. Acute (0.3-10 mg/kg, i.p.) and long-term administration (10 mg/kg, i.p., 21 days) of SSR149415 and SSR125543 reduced the FG 7142-induced increase in extracellular concentrations of acetylcholine in the hippocampus of anesthetized rats measured by microdialysis. By contrast acute and long-term administration of SSR149415 failed to reduce the FG 7142-induced increase in the release of norepinephrine in the cortex of freely moving rats. The present results demonstrate that the two compounds have similar profiles in a model of activation by an anxiogenic drug of the hippocampal cholinergic system and they suggest that SSR149415 and SSR125543 may have anti-stress anxiolytic and antidepressant effects via a mechanism of action different from classical benzodiazepine ligands and noradrenergic antidepressants.     

Are genes of human intelligence related to the metabolism of thyroid and steroids hormones? – Endocrine changes may explain human evolution and higher intelligence

We propose the hypothesis that genes of human intelligence are related with metabolism of thyroid and steroids hormones, which have a crucial role in brain development and function. First, there is evidence to support the idea that during hominid evolution small genetic differences were related with significant endocrine changes in thyroid and steroids hormones. Second, these neuroactive hormones are also related with unique features of human evolution such as body and brain size increase, penis and breast enlargement, pelvic sexual dimorphism, active sexuality, relative lack of hair and higher longevity. Besides underling many of the differences between humans and great apes, steroids hormones promote brain growth and development, are important in the myelination process, explain sexual dimorphisms in brain and intelligence and improve specific cognitive abilities in humans. Supporting our hypothesis, recent studies indicate differences in neuroactive hormones metabolism between humans and non-human primates. Furthermore, a link between X chromosome genes and sex steroids may explain why the frequency of genes affecting intelligence is so high on the X chromosome. This association suggests that, during hominid evolution, there was a positive feedback in both sexes on the same genes responsible for secondary sexual character development and intelligence. This interaction leads to acceleration of development of human brain and intelligence. Finally, we propose that neuroactive hormone therapy may provide significant improvement in some cognitive deficits in all stages of human life and in cases of neurodegenerative diseases. However, further investigation is needed, mainly in the enzymatic machinery, in order to understand the direct role of these hormones in intelligence.     

Our changing ideas about steroid effects on an ever-changing brain

Steroid hormone actions on gene expression in the brain provide a vast array of examples of environmentally-controlled gene expression. Recent studies of steroid hormone receptors and the effects they mediate have led to new findings which change our notions about the type and speed of plastic changes which the brain is capable of undergoing. We have found that estradiol and progesterone induce dendritic spines and new synapses as well as regulate oxytocin receptors in hypothalamus, whereas adrenal steroids affect neuronal survival and dendrite structure in the hippocampus as well as regulate several neurochemical processes throughout the brain related to the diurnal rhythm and adaptation to stress. Studies of estrogen and progesterone action in the hypothalamus have also shed some light on the nature of developmentally programmed sex differences in the brain. Moreover, recent work indicates that progesterone is a versatile steroid which not only affects gene expression but also produces effects via membrane receptors which alter release of neuroactive substances, chloride flux and the distribution of oxytocin receptors of the hypothalamus.     

Characterization of benzodiazepine receptor binding following kainic acid administration: an autoradiography study in rats

Aromatic solvents, such as toluene, can cause depression of the central nervous system functions in both solvent-exposed workers and abusers. The mechanism by which toluene produces its effects is generally thought to be similar to that produced by general anaesthetics, including inert gases and alcohols. However, whether lipophilic compounds indirectly influence activity by perturbing membrane lipids or bind directly to proteins remains a major question. In a recent study, the sigmoidal admission rate-dependence of inert gas anaesthetic potency has been suggested to possibly reflect a direct narcotic-protein interaction. Therefore, experiments have been carried out using seven input toluene flows of 0.5, 1, 2, 3, 4, 5 and 6 l/min. Our results indicate that as the rate of toluene delivery increased, the concentration of toluene required to produce anaesthetic effects increased. Although this was fitted relatively well with linear regression, this fitted better when using a sigmoidal model (r = 0.998 vs. r = 0.971, P < 0.01). In addition, comparison with previous data on nitrous oxide shows a striking similarity between plots (r = 0.991) which appears consistent with a similar site of action for both agents. We suggest that all classes of lipophilic agents could produce their inhibitory effects at similar 'non-specific' sites of action of finite size and limited occupancy.