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1. Introduction Menopause marks the cessation of menstruation due to the loss of follicular function (Santoro 2005; Brown and Gervais 2020) Some women in this stage report symptoms that prevent [...], No data in the literature have evaluated sex hormone dose escalation for treating abnormal sleep of ovariectomized rats--nor studies on the role of sex hormones in GABA synthesis of rats' sleep-related areas. The main aim of this study was to determine the maximum tolerated dose (MTD) of estradiol (ET), progesterone (PT), and the mixture of both (EPT) to restore normal sleep in a model of menopause in rats. The second purpose was to describe the in vitro activity of glutamate decarboxylase (GAD) in sleep-related brain areas in the presence or absence of sex hormones. A weekly dose-escalation design of ET, PT, or EPT was implemented in ovariectomized rats (six per group). Dose escalation continued until the dose at which 100% of the rats exhibited a state of "complete somnolence." Doses that were not toxic or did not show side effects were considered. For in vitro experiments, sleep-related brain areas were separated and incubated with radiolabeled glutamate. Estradiol (17[beta]-[E.sub.2]), progesterone (P), and pyridoxal phosphate (PLP) were added to this assay, and GAD activity was determined. Under the same conditions, a second test was carried out, but the P antagonist RU486 was added to assess the role of P in GAD activity. Ovariectomy increased periodic awakenings compared to those determined for the SHAM group. The EPT for ovariectomized rats was very effective by the fifth week in decreasing arousal and achieving a similar sleep behavior to the SHAM-control group. Rats tolerated the ET, PT, and EPT well to the maximum planned dose (0.66 mg/kg and 4.4 mg/kg, respectively). No lethal events occurred; the MTD was reached. The in vitro studies indicated that the presence of 17[beta]-[E.sub.2] plus P in the assay triggered the activity of isotype 65 GAD in all the studied brain areas. RU486 in the incubation medium blocked such activity; however, the action of isotype 67 GAD was not blocked by RU486. A dose-escalation model was determined; the MTD coincided with the maximum dose of ET and PT used. However, the EPT combination restored normal sleep in the menopause model compared to the SHAMs without toxic effects. The in vitro model demonstrated that 17[beta]-[E.sub.2] plus P presence in the assay increased the activity of [GAD.sub.65] in the studied brain tissues. Keywords: menopause, intermittent awakenings, glutamate decarboxylase activity, GABAergic brain regions, disturbed sleeping, female sex hormone.

Author(s): Pallabi Adak [sup.1] , Swagata Sinha [sup.2] , Nilanjana Banerjee [sup.1] Author Affiliations: (1) Manovikas Biomedical Research and Diagnostic Centre, , Manovikas Kendra, 482 Madudah, Plot I-24, Sector J, [...], In this pilot study, we aim to identify the role of few genetic variants of GABA-receptor type A subunits GABRB3 (rs4906902, rs7171660), GABRG3 (rs208129, rs140679), GABRA5 (rs 140681) in the aetiology of autism spectrum disorders in a population of West Bengal. 192 ASD probands, their parents and 184 ethnically-matched healthy controls were recruited for the study. The rs4906902G and the rs140679T conferred significant risk towards ASD. rs7171660 and rs140679 had transmission bias in the family. Neither alleles of rs 208129 and rs 140681 showed significant over-representation in either groups. All these variants were associated with at least one deficit in ASD-associated phenotypes like 'relating to people', 'Imitation', 'emotional response', 'body use', 'taste, smell, touch response' and 'activity levels'.

Introduction Schizophrenia is associated with impairments in executive functioning--particularly cognitive control. These deficits are present before illness onset (1) and are stable over the course of the illness, (2,3) showing [...], Background: The major excitatory and inhibitory neurometabolites in the brain, glutamate and y-aminobutyric acid (GABA), respectively, are related to the functional MRI signal. Disruption of resting-state functional MRI signals has been reported in psychosis spectrum disorders, but few studies have investigated the role of these metabolites in this context. Methods: We included 19 patients with first-episode psychosis and 21 healthy controls in this combined magnetic resonance spectroscopy (MRS) and resting-state functional connectivity study. All imaging was performed on a Siemens Magnetom 7 T MRI scanner. Both the MRS voxel and the seed for functional connectivity analysis were located in the dorsal anterior cingulate cortex (ACC). We used multiple regressions to test for an interaction between ACC brain connectivity, diagnosis and neurometabolites. Results: ACC brain connectivity was altered in first-episode psychosis. The relationship between ACC glutamate and ACC functional connectivity differed between patients with first-episode psychosis and healthy controls in the precuneus, retrosplenial cortex, supramarginal gyrus and angular gyrus. As well, the relationship between ACC GABA and ACC functional connectivity differed between groups in the caudate, putamen and supramarginal gyrus. Limitations: We used a small sample size. As well, although they were not chronically medicated, all participants were medicated during the study. Conclusion: We demonstrated a link between the major excitatory and inhibitory brain metabolites and resting-state functional connectivity in healthy participants, as well as an alteration in this relationship in patients with first-episode psychosis. Combining data from different imaging modalities may help our mechanistic understanding of the relationship between major neurometabolites and brain network dynamics, and shed light on the pathophysiology of first-episode psychosis.

Introduction Mood disorders, such as depression and anxiety, are closely related to bone metabolism abnormalities (1-3) and can lead to low bone mass and increased risk of fracture (4, 5). [...], Homeostasis of bone metabolism is regulated by the central nervous system, and mood disorders such as anxiety are associated with bone metabolism abnormalities, yet our understanding of the central neural circuits regulating bone metabolism is limited. Here, we demonstrate that chronic stress in crewmembers resulted in decreased bone density and elevated anxiety in an isolated habitat mimicking a space station. We then used a mouse model to demonstrate that GABAergic neural circuitry in the ventromedial hypothalamus (VMH) mediates chronic stress-induced bone loss. We show that GABAergic inputs in the dorsomedial VMH arise from a specific group of somatostatin neurons in the posterior region of the bed nucleus of the stria terminalis, which is indispensable for stress-induced bone loss and is able to trigger bone loss in the absence of stressors. In addition, the sympathetic system and glutamatergic neurons in the nucleus tractus solitarius were employed to regulate stress-induced bone loss. Our study has therefore identified the central neural mechanism by which chronic stress-induced mood disorders, such as anxiety, influence bone metabolism.

Introduction Up to 44% of patients with major depressive disorder (MDD) experience treatment-resistant depression (TRD): illness that fails to respond to multiple medication trials. (1) Among patients with MDD, those [...], Background: The therapeutic mechanism of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) may involve modulation of [gamma]-aminobutyric acid (GABA) levels. We used proton magnetic resonance spectroscopy (MRS) to assess changes in GABA levels at the site of rTMS in the left dorsolateral prefrontal cortex (DLPFC). Methods: In 26 adults with TRD, we used Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) spectral-editing MRS to measure GABA in the left DLPFC before and after standard clinical treatment with rTMS. All participants but 1 were medicated, including 12 patients on GABA agonist agents. Results: Mean GABA in the DLPFC increased 10.0% (p = 0.017) post-rTMS in the overall sample. As well, GABA increased significantly in rTMS responders (n = 12; 23.6%, p = 0.015) but not in nonresponders (n = 14; 4.1%, p = not significant). Changes in GABA were not significantly affected by GABAergic agonists, but clinical response was less frequent (p = 0.005) and weaker (p = 0.035) in the 12 participants who were receiving GABA agonists concomitant with rTMS treatment. Limitations: This study had an open-label design in a popul ation receiving naturalistic treatment. Conclusion: Treatment using rTMS was associated with increases in GABA levels at the stimulation site in the left DLPFC, and the degree of GABA change was related to clinical improvement. Participants receiving concomitant treatment with a GABA agonist were less likely to respond to rTMS. These findings were consistent with earlier studies showing the effects of rTMS on GABA levels and support a GABAergic model of depression.

Introduction Transcranial magnetic stimulation (TMS) is an effective treatment for major depressive disorder (MDD), particularly in individuals resistant to first-line antidepressants. (1-3) Effect sizes of TMS from recent meta-analyses range [...], Background: GABAergic and glutamatergic neurotransmitter systems are central to the pathophysiology of depression and are potential targets of repetitive transcranial magnetic stimulation (rTMS). We assessed the effect of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) of patients with major depressive disorder on the levels of medial prefrontal cortex (MPFC) γ-aminobutyric acid (GABA) and the combined resonance of glutamate and glutamine (Glx) as assessed in vivo with proton magnetic resonance spectroscopy (¹H MRS). Methods: Currently depressed individuals between the ages of 23 and 68 years participated in a 5-week naturalistic, open-label treatment study of rTMS, with ¹H MRS measurements of MPFC GABA and Glx levels at baseline and following 5 weeks of the rTMS intervention. We applied rTMS pulses over the left DLPFC at 10 Hz and 80%-120% of motor threshold for 25 daily sessions, with each session consisting of 3000 pulses. We assessed therapeutic response using the 24-item Hamilton Rating Scale for Depression (HAMD24). The GABA and Glx levels are expressed as ratios of peak areas relative to the area of the synchronously acquired and similarly fitted unsuppressed voxel water signal (W). Results: Twenty-three currently depressed individuals (7 men) participated in the study. GABA/W in the MPFC increased 13.8% (p = 0.013) in all depressed individuals. There were no significant effects of rTMS on Glx/W. GABA/W and Glx/W were highly correlated in severely depressed patients at baseline but not after TMS. Limitations: The primary study limitations are the open-label design and the inclusion of participants currently taking stable regimens of antidepressant medications. Conclusion: These results implicate GABAergic and glutamatergic systems in the mechanism of action of rTMS for major depression, warranting further investigation in larger samples.

Introduction Studies performed previously in anesthetized rabbits demonstrated that during pulmonary lymphatic obstruction (PLO), there is an increase in urine flow (Ravi et al. 1997; McCormick et al. 2004, 2005). [...], The changes in urine flow and renal sympathetic nerve activity (RSNA) due to pulmonary lymphatic obstruction (PLO) were examined in anesthetized, artificially ventilated New Zealand white rabbits. PLO was produced by pressurizing an isolated pouch created in the right external jugular vein at the points of entry of the right lymphatic ducts. During this maneuver, urine flow increased from 8.5 ± 0.3 mL/10 min to 12 ± 0.5 mL/10 min (P < 0.0001) and RSNA increased from 24.0 ± 4 to 40.0 ± 5 µVxs (P < 0.0001). Bilateral lesioning of the paraventricular nucleus (PVN) of the hypothalamus or cervical vagotomy abolished these responses. PLO increased c-fos gene expression in the PVN. The increase in urine flow due to PLO was attenuated by muscimol and abolished by kynurenic acid microinjections into the PVN. The results show that (i) neurons in the PVN are an important relay site in the reflex arc, which is activated by PLO; and (ii) this activation is regulated by glutamatergic and partly by GABAergic input to the PVN. Key words: GABA, glutamate, hypothalamus, kidney, lung, lymphatics, vagus. Nous avons etudie les variations du debit urinaire et de l'activite des nerfs sympathiques renaux causees par l'obstruction des vaisseaux lymphatiques pulmonaires chez des lapins blancs de Nouvelle-Zelande anesthesies et sous ventilation artificielle. Nous avons provoque l'obstruction des vaisseaux lymphatiques pulmonaire en augmentant la pression dans une poche menagee a l'interieur de la veine jugulaire externe droite, a l'embouchure des canaux lymphatiques droits. Au cours de cette intervention, le debit urinaire a augmente de 8,5 ± 0,3 a 12 ± 0,5 mL/10 min (P < 0,0001) et l'activite des nerfs sympathiques renaux de 24,0 ± 4 a 40,0 ±5 µVxs (P < 0,0001). La lesion bilaterale du noyau paraventriculaire de l'hypothalamus ou la vagotomie bilaterale au niveau cervical ont aboli ces reponses. Par ailleurs, l'obstruction des vaisseaux lymphatiques pulmonaires a augmente l'expression du gene c-fos dans le noyau paraventriculaire. Enfin, l'augmentation du debit urinaire causee par l'obstruction des vaisseaux lymphatiques pulmonaires a ete attenuee par l'administration de muscimol et supprimee par des micro-injections d'acide kynurenique dans le noyau paraventriculaire. Les resultats montrent (i) que les neurones du noyau paraventriculaire correspondent a un relais important dans l'arc reflexe active par l'obstruction des vaisseaux lymphatiques pulmonaires; et (ii) que cette activation est reglee par la contribution du systeme glutamatergique et partiellement par celle du systeme GABAergique a l'activite du noyau paraventriculaire. [Traduit par la Redaction] Mots-cles: GABA, glutamate, hypothalamus, rein, poumon, vaisseaux lymphatiques, nerf vague.

Body fluid homeostasis regulates the internal salt and water balance; as this balance shifts, the brain senses these changes and triggers specific goal-oriented intake behaviours (2, 3). For instance, salt-deprived [...], Thirst is the basic instinct to drink water. Previously, it was shown that neurons in several circumventricular organs of the hypothalamus are activated by thirst-inducing conditions (1). Here we identify two distinct, genetically separable neural populations in the subfornical organ that trigger or suppress thirst. We show that optogenetic activation of subfornical organ excitatory neurons, marked by the expression of the transcription factor ETV-1, evokes intense drinking behaviour, and does so even in fully water-satiated animals. The light-induced response is highly specific for water, immediate and strictly locked to the laser stimulus. In contrast, activation of a second population of subfornical organ neurons, marked by expression of the vesicular GABA transporter VGAT, drastically suppresses drinking, even in water-craving thirsty animals. These results reveal an innate brain circuit that can turn an animal's water-drinking behaviour on and off, and probably functions as a centre for thirst control in the mammalian brain.

Introduction Studies have shown that the GABA system is associated with anxiety and depression, and that some neuroactive steroids like progesterone and its metabolite allopregnanolone could play an important role [...], The aim of this study was to evaluate the effect of progesterone on the protein expression of α4 subunit of GABA(A) receptor, serotonin transporter (SERT), Akt, Erk, and caspase-3 in the olfactory bulb (OB) of female rats exposed to the forced swimming test (FST). Female rats were injected daily with progesterone (0.4 mg/kg body mass) or vehicle during 2 complete oestrous cycles and exposed to the FST, and the protein expression of GABA(A) receptor α4 subunit, SERT, Akt, Erk, and caspase-3 in the OB were evaluated. Progesterone increased the expression of the α4 subunit in the right OB and decreased its expression in the left OB, although it did not change the expression of other proteins. In summary, our findings indicate that progesterone has an asymmetric modulatory effect on the expression of GABA(A) receptor α4 subunit in the OB. This effect could be related to the antidepressant-like effect of progesterone in female rats. Key words: depression, steroids, forced swimming test, serotonin transporter (SERT), neuroprotection. Le but de cette etude etait d'evaluer l'effet de la progesterone sur l'expression proteique de la sous-unite α4 du recepteur GABA(A), du transporteur de la serotonine (SERT), d'Akt, d'Erk et de la caspase-3 dans le bulbe olfactif (BO) de rats femelles exposees a un test de la nage forcee (FST, forced swimming test). Les rats femelles ont recu une injection quotidienne de progesterone (0,4 mg/kg de masse corporelle) ou de vehicule durant deux cycles restraux complets et elles ont ete exposees au FST, a la suite de quoi l'expression proteique de la sous-unite α4 du recepteur GABA(A), du transporteur de la serotonine (SERT), d'Akt, d'Erk et de la caspase-3 dans le BO a ete evaluee. La progesterone accroissait l'expression de la sous-unite a 4 dans le BO droit et diminuait son expression dans le BO gauche, mais elle ne modifiait pas l'expression des autres proteines. En resume, les resultats des auteurs indiquent que la progesterone exerce un effet modulateur asymetrique sur l'expression de la sous-unite α4 du recepteur GABA(A) dans le BO. Cet effet pourrait etre lie a l'effet de type antidepresseur de la progesterone chez les rats femelles. [Traduit par la Redaction] Mots-cles: depression, steroides, test de la nage forcee, transporteur de serotonine (SERT), neuroprotection.

Introduction The major neurotransmitter implicated in the etiology of anxiety disorders is 7-amino butyric acid (GABA) (Treiman 2001; Lydiard 2003). GABA is the major inhibitory neurotransmitter in the central nervous [...], The mode of action of the anxiolytic medicinal plant Souroubea sympetala was investigated to test the hypothesis that extracts and the active principle act at the pharmacologically important [GABA.SUB.A]-benzodiazepine ([GABA.sub.A]-BZD) receptor. Leaf extracts prepared by ethyl acetate extraction or supercritical extraction, previously determined to have 5.54 mg/g and 6.78 mg/g of the active principle, betulinic acid, respectively, reduced behavioural parameters associated with anxiety in a rat model. When animals were pretreated with the [GABA.sub.A]-BZD receptor antagonist flumazenil, followed by the plant extracts, or a more soluble derivative of the active principle, the methyl ester of betulinic acid (MeBA), flumazenil eliminated the anxiety- reducing effect of plant extracts and MeBA, demonstrating that S. sympetala acts via an agonist action on the [GABA.sub.A]-BZD receptor. An in vitro [GABA.sub.A]-BZD competitive receptor binding assay also demonstrated that S. sympetala extracts have an affinity for the [GABA.sub.A]-BZD receptor, with an [EC.sub.50] value of 123 p.g/mL (EtOAc leaf extract) and 154 µg/mL (supercritical CO2 extract). These experiments indicate that S. sympetala acts at the [GABA.sub.A]-BZD receptor to elicit anxiolysis. Key words: natural health product, anxiety, pharmacology, betulinic acid, methyl ester of betulinic acid. Le mode d'action de la plante medicinale anxiolytique Souroubea sympetala a ete etudie afin de verifier l'hypothese que les extraits et le principe actif de la plante agissent sur le recepteur [GABA.SUB.A]-benzodiazepine ([GABA.sub.A]-BZD), un recepteur d'importance clinique. Des extraits de feuilles prepares par extraction a l'acetate d'ethyle ou par extraction supercritique, dont on a determine qu'ils contenaient respectivement 5,54 mg/g et 6,78 mg/g de principe actif, l'acide betulinique, reduisaient les parametres comportementaux associes a l'anxiete chez le rat utilise comme modele. Lorsque les animaux etaient pretraites avec un antagoniste du recepteur [GABA.sub.A]-BZD, le flumazenil, et des extraits de la plante ou d'un derive plus soluble du principe actif, l'ester de methyle de l'acide betulinique (MeBA), le flumazenil eliminait l'effet anxiolytique des extraits de la plante, demontrant ainsi que S. sympetala agit par une action agoniste du recepteur [GABA.sub.A]-BZD. Un test de competition de liaison du recepteur [GABA.sub.A]-BZD realise in vitro a aussi demontre que les extraits de S. sympetala ont une affinite pour le recepteur [GABA.sub.A]-BZD, avec des valeurs de [EC.sub.50] de 123 pg/mL (extrait de feuilles a l'acetate d'ethyle) et 154 pg/mL (extrait supercritique au C[O.sub.2]). Ces experiences indiquent que S. sympetala agit sur le recepteur [GABA.sub.A]-BZD pour provoquer un effet anxiolytique. [Traduit par la Redaction] Mots-cles: produit de sante naturel, anxiete, pharmacologie, acide betulinique, ester de methyle d'acide betulinique.

Introduction Diabetic neuropathy, characterized by progressive sensory loss, is a common long-term complication of diabetes mellitus (Pirart 1978; Dyck et al. 1993). Chronic hyperglycemia in diabetic patients can induce neuropathic [...], This study aimed to investigate the effect of baclofen, a γ-ammobutyric acid B (GABAB) receptor agonist, on the expression of p-CREB and NR2B in the spinal dorsal horn of rats with diabetic neuropathic pain (DNP). The DNP rats, which were successfully induced with streptozocin, were distributed among 3 groups that were treated with saline (D1 group), baclofen (D2 group), or CGP55845 + baclofen (D3 group) continuously for 4 days. The rats induced with saline and subsequently treated with saline were used as controls (C group). The times for the paw withdrawal threshold and thermal withdrawal latency of the D1 group were lower than those for the C group, and were significantly increased after baclofen treatment, but not when GABA receptor was pre-blocked with CGP55845 (D3 group). Increased protein expression levels of NR2B and p-CREB and mRNA levels of NR2B were found in the D1 group when compared with the controls. Baclofen treatment significantly suppressed their expression, bringing it close to the levels of controls. However, in the D3 group, the expression of p-CREB and NR2B were still significantly higher than that of the controls. Activation of GABAB receptor by baclofen attenuates diabetic neuropathic pain, which may partly be accomplished via down-regulating the expression of p-CREB and NR2B. Key words: diabetic neuropathic pain, γ-aminobutyric acid receptor, cyclic adenosine monophosphate response element binding protein, N-methyl-D-aspartate receptor. Cette etude visait a examiner l'effet du baclofene, un agoniste du recepteur de l'acide γ-aminobutyrique B (GABAB), sur l'expression de p-CREB et de NR2B dans la corne dorsale de la moelle de rats souffrant de douleur neuropathique diabetique (DND). Les rats DND, dont le diabete a ete induit avec succes par la streptozotocine, ont ete repartis en 3 groupes traites a la saline (groupe D1), au baclofene (groupe D2) et au CGP55845 + baclofene (goupe D3) en continu pendant 4 jours. Les rats'induits' par la saline et traites subsequemment a la saline ont ete utilises comme controles (groupe C). Le seuil de retrait de la patte et le temps de latence de retrait au stimulus thermique du groupe D1 etaient plus faibles que ceux du groupe C, lesquels etaient significativement accrus apres le traitement au baclofene, mais pas si le recepteur GABA avait ete bloque prealablement avec le CGP55845 (groupe D3). Des niveaux eleves d'expression de NR2B et de p-CREB, et d'ARNm de NR2B ont ete observes chez le groupe D1 comparativement aux controles. Le traitement au baclofene diminuait de facon remarquable leur expression qui se trouvait par la suite pres des niveaux des controles. Cependant, chez le groupe D3, l'expression de p-CREB et de NR2B demeurait significativement plus elevee que celle des controles. L'activation du recepteur GABA par le baclofene pourrait attenuer la douleur neuropathique diabetique, en partie par la regulation a la baisse de l'expression de p-CREB et de NR2B. [Traduit par la Redaction] Mots-cles: douleur neuropathique diabetique, recepteur de l'acide γ-aminobutyrique, proteine liant l'element de reponse a l'adenosine monophosphate cyclique, recepteur du N-methyl-D-aspartate.