Brain Glutamate Levels Research Articles

Glutamate dynamics and BOLD response during OCD symptom provocation in the lateral occipital cortex: A 7 Tesla fMRI-fMRS study

Obsessive-compulsive disorder (OCD) is linked with dysfunction in frontal-striatal, fronto-limbic, and visual brain regions. Research using proton magnetic resonance spectroscopy (1H-MRS) suggests that altered neurometabolite levels, like glutamate, may contribute to this dysfunction. However, static neurometabolite levels in OCD patients have shown inconsistent results, likely due to previous studies' limited focus on neurometabolite dynamics. We employ functional MRS (fMRS) and functional magnetic resonance imaging (fMRI) to explore these dynamics and brain activation during OCD symptom provocation.We utilized a combined 7-tesla fMRI-fMRS setup to examine task-related BOLD response and glutamate changes in the lateral occipital cortex (LOC) of 30 OCD participants and 34 matched controls during an OCD-specific symptom provocation task. The study examined main effects and between-group differences in brain activation and glutamate levels during the task.A whole sample task-effects analysis on data meeting predefined quality criteria showed significant glutamate increases (n = 41 (22 OCD, 19 controls), mean change: 3.2 %, z = 3.75, p < .001) and task activation (n = 54 (26 OCD, 28 controls), p < .001) in the LOC during OCD blocks compared to neutral blocks. However, no differences in task-induced glutamate dynamics or activation between groups were found, nor a correlation between glutamate levels and task activation.We were able to measure task-induced increases in glutamate and BOLD levels, emphasizing its feasibility for OCD research. The absence of group differences highlights the need for further exploration to discern to what extent neurometabolite dynamics differ between OCD patients and controls. Once established, future studies can use pre-post intervention fMRS-fMRI to probe the effects of therapies modulating glutamate pathways in OCD.

The Role of Vitamin C on ATPases Activities in Monosodium Glutamate-Induced Oxidative Stress in Rat Striatum and Cerebellum.

Monosodium glutamate (MSG) is a silent excitotoxin used as a flavour enhancer but exerts serious health hazards to consumers. MSG plays a role in neuronal function as the dominant excitatory neurotransmitter. It is transferred into the blood and ultimately increases brain glutamate levels, causing functional disruptions notably via oxidative stress. The study evaluated the toxic effect of high consumption of MSG and the modulatory role of vitamin C on ATPase activities in the striatum and cerebellum of male Wistar rats for five weeks. Rats were grouped into four (A-D): group A was fed with rat's show only; Group B was fed with diet containing 15% MSG; Group C was treated with vitamin C (200mg/kg b.wgt orally in 0.9% saline solution) only for 3weeks; and group D rats were fed with MSG and vitamin C. The findings show that MSG does not affect body and cerebellum weights but increases striatal weight. MSG increases the malondialdehyde (MDA) level and significantly decreases catalase (CAT) and superoxide dismutase (SOD) activities and glutathione (GSH) levels. MSG significantly impaired striatal and cerebellar ATPases activities (Na+/K+-, Ca2+-, Mg2+- and total ATPases). Vitamin C treatment abolishes MSG-induced oxidative stress and improves ATPase activities. The findings show that vitamin C has beneficial effects in improving the functions of membrane-bound ATPases against MSG toxicity in rat's striatum and cerebellum.

Ovariectomy exacerbates the disturbance of excitation- inhibition balance in the brain of APP/PS-1/tau mice.

The prevalence of Alzheimer's disease (AD) is significantly gender-differentiated, with the number of female AD patients far exceeding that of males, accounting for two-thirds of the total prevalence. Although postmenopausal AD mice have been shown to have more prominent pathologic features and memory impairments than normal AD mice, the relevant molecular mechanisms leading to these outcomes have not been well elucidated. In the present study, we used the disturbance of excitation-inhibition balance in the postmenopausal brain as an entry point to explore the link between estrogen deficiency, disorders of the glutamatergic-GABAergic nervous system, and memory impairment. Wild-type (WT) mice and APP/PS1/tau (3 × Tg-AD) mice (10 months old) were randomly divided into four groups: WT+Sham group, WT+OVX group, 3 × Tg-AD+Sham group and 3 × Tg-AD+OVX group. Ovariectomy (OVX) was performed in the WT+OVX group and the 3 × Tg-AD+OVX group, and sham surgery was performed in the WT+Sham group and the 3 × Tg-AD+Sham group. The learning and memory ability and the anxiety and depression-like behavior changes of mice were evaluated by behavioral experiments, and the association between estrogen-estrogen receptors pathway and glutamatergic/GABAergic nervous system and female AD was evaluated by neurochemical experiments. In WT and 3 × Tg-AD mice, OVX resulted in impaired learning and memory abilities and anxiety and depression-like behaviors; reduced estrogen levels and downregulated the expression of estrogen receptors; upregulated the expression of amyloid-β, amyloid precursor protein, presenilin 1, and p-tau; upregulated the expression of Bcl-2-associated X protein and downregulated the expression of B-cell lymphoma-2, promoting cell apoptosis; reduced the number of neuronal dendrites and downregulated the expression of postsynaptic density protein-95; more importantly, OVX increased brain glutamate levels but downregulated the expression of N-methyl-D-aspartate receptor-2B, excitatory amino acid transporter 1, excitatory amino acid transporter 2, γ-aminobutyric acid receptor-A and γ-aminobutyric acid receptor-B. Our results suggested that OVX-induced estrogen-estrogen receptors pathway disruption caused learning and memory impairment and anxiety and depression-like behaviors, upregulated the expression of AD pathological markers, promoted apoptosis, destroyed neuronal structure, and most importantly, caused glutamatergic/GABAergic nervous system disorders.

Do toenail manganese and iron levels reflect brain metal levels or brain metabolism in welders?

Inhalation of welding fumes can cause metal accumulation in the brain, leading to Parkinsonian-like symptoms. Metal accumulation and altered neurochemical profiles have been observed using magnetic resonance imaging (MRI) in highly exposed welders, being associated with decreased motor function and cognition. While MRI is impractical to use as a health risk assessment tool in occupational settings, toenail metal levels are easier to assess and have been demonstrated to reflect an exposure window of 7–12 months in the past. Yet, it is unclear whether toenail metal levels are associated with brain metal levels or changes in metabolism, which are the root of potential health concerns. This study investigates whether toenail manganese (Mn) and iron (Fe) levels, assessed at several time points, correlate with brain Mn and Fe levels, measured by MRI, as well as brain GABA, glutamate (Glu), and glutathione (GSH) levels, measured by Magnetic Resonance Spectroscopy (MRS), in seventeen Mn-exposed welders. Quantitative T1 and R2* MRI maps of the whole brain, along with GABA, Glu, and GSH MRS measurements from the thalamus and cerebellum were acquired at baseline (T0). Toenail clippings were collected at T0 and every three months after the MRI for a year to account for different exposure periods being reflected by toenail clippings and MRI. Spearman correlations of toenail metal levels were run against brain metal and metabolite levels, but no significant associations were found for Mn at any timepoint. Cerebellar GSH positively correlated with toenail Fe clipped twelve months after the MRI (p = 0.05), suggesting an association with Fe exposure at the time of the MRI. Neither thalamic GABA nor Glu correlated with toenail Fe levels. In conclusion, this study cannot support toenail Mn as a proxy for brain Mn levels or metabolic changes, while toenail Fe appears linked to brain metabolic alterations, underscoring the importance of considering other metals, including Fe, in studying Mn neurotoxicity.

Glutamatergic neurotransmission in schizophrenia: A systematic review and quantitative synthesis of proton magnetic resonance spectroscopy studies across schizophrenia spectrum disorders.

Studies using proton magnetic resonance spectroscopy reveal substantial inconsistencies in the levels of brain glutamate, glutamine and glutamate + glutamine across schizophrenia spectrum disorders. This systematic review employs qualitative and quantitative methods to analyse the patterns and relationships between glutamatergic metabolites, schizophrenia spectrum disorders and brain regions. A literature search was conducted using various databases with keywords including glutamate, glutamine, schizophrenia, psychosis and proton magnetic resonance spectroscopy. Inclusion criteria were limited to case-control studies that reported glutamatergic metabolite levels in adult patients with a schizophrenia spectrum disorder diagnosis - i.e. first-episode psychosis, schizophrenia, treatment-resistant schizophrenia and/or ultra-treatment-resistant schizophrenia - using proton magnetic resonance spectroscopy at 3 T or above. Pooled study data were synthesized and analysed. A total of 92 studies met the inclusion criteria, including 2721 healthy controls and 2822 schizophrenia spectrum disorder participants. Glu levels were higher in the basal ganglia, frontal cortex and medial prefrontal of first-episode psychosis participants, contrasting overall lower levels in schizophrenia participants. For Gln, strong differences in metabolite levels were evident in the basal ganglia, dorsolateral prefrontal cortex and frontal cortex, with first-episode psychosis showing significantly higher levels in the basal ganglia. In glutamate + glutamine, higher metabolite levels were found across schizophrenia spectrum disorder groups, particularly in the basal ganglia and dorsolateral prefrontal cortex of treatment-resistant schizophrenia participants. Significant relationships were found between metabolite levels and medication status, clinical measures and methodological variables. The review highlights abnormal glutamatergic metabolite levels throughout schizophrenia spectrum disorders and in specific brain regions. The review underscores the importance of standardized future research assessing glutamatergic metabolites using proton magnetic resonance spectroscopy due to considerable literature heterogeneity.

Assessing effects of tamoxifen on tolerance, dependence, and glutamate and glutamine levels in frontal cortex and hippocampus in chronic morphine treatment

Tamoxifen has been shown to reduce glutamate release from presynaptic glutamatergic nerves and reverse tolerance to morphine-induced respiratory depression. Changes in glutamatergic neurotransmission in the central nervous system contribute to morphine tolerance, dependence, and withdrawal. This study, therefore, evaluated effects of tamoxifen on development of analgesic tolerance and dependence, and brain glutamate and glutamine levels in chronic morphine administration. Mice implanted with placebo or morphine pellets were injected with tamoxifen (0.6–2 mg/kg) or vehicle twice daily for 3 days. Nociceptive response was evaluated in the hot plate and tail immersion tests, 4, 48 and 72 h post-implant, and following a challenge dose of morphine (10 mg/kg). Withdrawal signs were determined after naloxone (1 mg/kg) administration. Morphine increased nociceptive threshold which declined over time. At 72 h, acute morphine elicited tolerance to the analgesic effect in the hot plate test in vehicle or tamoxifen administered animals. In the tail immersion test, however, tolerance to morphine analgesia was observed in tamoxifen, but not vehicle, co-administration. Tamoxifen did not reduce withdrawal signs. In contrast to previous reports, glutamate and glutamine levels in the hippocampus and frontal cortex did not change in the morphine-vehicle group. Confirming previous findings, tamoxifen (2 mg/kg) decreased glutamate and glutamine concentrations in the hippocampus in animals with placebo pellets. Both doses of tamoxifen significantly changed glutamate and/or glutamine concentrations in both regions in morphine pellet implanted animals. These results suggest that tamoxifen has no effect on dependence but may facilitate tolerance development to the antinociception, possibly mediated at the spinal level, in chronic morphine administration.

Neurochemical Effects of the Adipokinetic Hormone/Red Pigment Concentrating Hormone Family of Peptides in MK-801-Induced Schizophrenia Rat Model

Objective: Adipokinetic hormone (AKH) plays a role in sugar and lipid metabolism in insects. Previous studies of AKH showed memory improvements in a schizophrenia rat model that displayed memory impairment and reduced depression in a rat olfactory bulbectomy model. In this study, we investigated the effects of the adipokinetic hormone/red pigment-concentrating hormone (AKH/RPCH) family of peptides on brain neurotransmitter levels and brain neurochemistry in a schizophrenia rat model. Materials and Methods: We administered AKH/RPCH peptides for 4 days sub-chronically, both in naive rats and also in the MK-801-induced schizophrenia rat model. Liquid chromatography-mass spectrometry apparatus was used for targeted and untargeted analysis of rat neurochemistry. Results: Increased brain glutamate levels characteristic of MK-801 peptide-treated rats were significantly reduced by AKH. Furthermore, AKH also increased brain dopamine levels in both naive and MK-801 rats. Metabolomic studies have shown that AKH affects lipid and glutamate metabolism, while hypertrehalosaemic hormone plays a role in sugar metabolism and inflammation. Conclusion: According to our results, AKH might affect dopaminergic and glutamatergic systems and reverse the effects of MK-801, possibly affecting NMDA receptors.

FORMULATION AND EVALUATION OF DISPERSIBLE TABLETS OF FLAVONOID PGAL ISOLATED FROM SARACA ASOCA LEAVES

Objective: The study aimed to design and evaluate a dispersible tablet of flavonoid PGAL isolated from Saraca asoca leaves for antidepressant activity. Methods: The phytoconstituent was isolated from a methanolic extract of Saraca asoca leaves using silica gel column (60-120 mesh) chromatography. The dispersible tablets were prepared by direct compression and then evaluated for various tablet evaluation parameters and antidepressant activity, performing Tail Suspension Test (TST), Forced Swim Test (FST), Locomotion activity, Brain glutamate level and brain nitrite level. Results: Hardness of 2.85±0.13 kg/cm2 to 3.25±0.15 kg/cm2 and friability of 0.35% to 0.48% indicate that the prepared tablets were mechanically sound. Test for weight variation was also within tolerance limits, i.e. 2.04% to 4.25% difference in weight of the tablet from the average weight of 10 tablets. The tablets also passed the test for drug content uniformity, 97.35% to 100.35%, i.e. always within the prescribed limits of 95% to 105%. Disintegration time, 2 min to 2.75 min, and dispersion time, 3.25 min to 3.75 min, were also exemplary. The antidepressant activity was displayed by the optimized formulation as indicated by a significant decrease (p&lt;0.05) in immobility time in TST as well as FST; a significant decrease (p&lt;0.05) in the level of brain tissue glutamate as well as nitrite in PGAL formulation treated mice when compared with negative control, as did by standard drug fluoxetine. Conclusion: The formulation has been optimized based on dispersion time. The formulation with minimum dispersion time, i.e. F1, has been considered an optimized formulation. The prepared optimized formulation was found to comply with all physical parameters and antidepressant activity.

The association between peripheral inflammation, brain glutamate and antipsychotic response in Schizophrenia: Data from the STRATA collaboration

Glutamate and increased inflammation have been separately implicated in the pathophysiology of schizophrenia and the extent of clinical response to antipsychotic treatment. Despite the mechanistic links between pro-inflammatory and glutamatergic pathways, the relationships between peripheral inflammatory markers and brain glutamate in schizophrenia have not yet been investigated. In this study, we tested the hypothesis that peripheral levels of pro-inflammatory cytokines would be positively associated with brain glutamate levels in schizophrenia. Secondary analyses determined whether this relationship differed according to antipsychotic treatment response. The sample consisted of 79 patients with schizophrenia, of whom 40 were rated as antipsychotic responders and 39 as antipsychotic non-responders. Brain glutamate levels were assessed in the anterior cingulate cortex (ACC) and caudate using proton magnetic resonance spectroscopy (1H-MRS) and blood samples were collected for cytokine assay on the same study visit (IL-6, IL-8, IL-10, TNF- α and IFN-γ). Across the whole patient sample, there was a positive relationship between interferon-gamma (IFN-γ) and caudate glutamate levels (r = 0.31, p = 0.02). In the antipsychotic non-responsive group only, there was a positive relationship between interleukin-8 (IL-8) and caudate glutamate (r = 0.46, p = 0.01). These findings provide evidence to link specific peripheral inflammatory markers and caudate glutamate in schizophrenia and may suggest that this relationship is most marked in patients who show a poor response to antipsychotic treatment.

The Integrity of the Blood-Brain Barrier as a Critical Factor for Regulating Glutamate Levels in Traumatic Brain Injury.

A healthy blood-brain barrier (BBB) shields the brain from high concentrations of blood glutamate, which can cause neurotoxicity and neurodegeneration. It is believed that traumatic brain injury (TBI) causes long-term BBB disruption, subsequently increasing brain glutamate in the blood, in addition to increased glutamate resulting from the neuronal injury. Here, we investigate the relationship between blood and brain glutamate levels in the context of BBB permeability. Rats exposed to BBB disruption through an osmotic model or TBI and treated with intravenous glutamate or saline were compared to control rats with an intact BBB treated with intravenous glutamate or saline. After BBB disruption and glutamate administration, the concentrations of glutamate in the cerebrospinal fluid and blood and brain tissue were analyzed. The results showed a strong correlation between the brain and blood glutamate concentrations in the groups with BBB disruption. We conclude that a healthy BBB protects the brain from high levels of blood glutamate, and the permeability of the BBB is a vital component in regulating levels of glutamate in the brain. These findings bring a new approach to treating the consequences of TBI and other diseases where long-term disruption of the BBB is the central mechanism of their development.

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = −0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = −0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = −0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = −0.02, p < 0.001) and frontal white matter Glx (z = −0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

Blood glutamate scavenging as a novel glutamate-based therapeutic approach for post-traumatic brain injury anxiety and social impairment

Traumatic brain injury (TBI) is a serious condition that is associated with an increased risk of severe, long-term psychiatric consequences. Drugs that target the glutamatergic system have proven successful in treating both TBI and many of its psychiatric sequelae. Blood glutamate scavengers (BGS) cause a decrease in blood glutamate levels, leading to a reduction in glutamate’s concentration gradient from the brain to the blood and decreased levels of brain glutamate. This study evaluated the BGS pyruvate as a treatment for TBI-related neuropsychiatric conditions in a rat model. 213 rats were divided into four groups in a 2 × 2 design: Sham or TBI rats treated with pyruvate or control treatment. Magnetic resonance imaging, neurological status, brain glutamate and blood glutamate levels were assessed following the injury. Four weeks after the start of treatment, all rats underwent behavioral tests to assess anxious behavior and social impairment (aggressive and hierarchical behavior). Rats responded positively to pyruvate in several tasks, lowering brain glutamate levels and reducing anxiety and depression, as well as modulating TBI-related changes in social behavior. Glutamate scavenging with pyruvate may be an effective therapeutic option for post-TBI behavioral changes by reducing associated elevations in brain glutamate levels.

Glutamatergic synapse in autism: a complex story for a complex disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathophysiological mechanisms are still unclear. Hypotheses suggest a role for glutamate dysfunctions in ASD development, but clinical studies investigating brain and peripheral glutamate levels showed heterogenous results leading to hypo- and hyper-glutamatergic hypotheses of ASD. Recently, studies proposed the implication of elevated mGluR5 densities in brain areas in the pathophysiology of ASD. Thus, our objective was to characterize glutamate dysfunctions in adult subjects with ASD by quantifying (1) glutamate levels in the cingulate cortex and periphery using proton magnetic resonance spectroscopy and metabolomics, and (2) mGluR5 brain density in this population and in a validated animal model of ASD (prenatal exposure to valproate) at developmental stages corresponding to childhood and adolescence in humans using positron emission tomography. No modifications in cingulate Glu levels were observed between individuals with ASD and controls further supporting the difficulty to evaluate modifications in excitatory transmission using spectroscopy in this population, and the complexity of its glutamate-related changes. Our imaging results showed an overall increased density in mGluR5 in adults with ASD, that was only observed mostly subcortically in adolescent male rats prenatally exposed to valproic acid, and not detected in the stage corresponding to childhood in the same animals. This suggest that clinical changes in mGluR5 density could reflect the adaptation of the glutamatergic dysfunctions occurring earlier rather than being key to the pathophysiology of ASD.

Clock gene-dependent glutamate dynamics in the bean bug brain regulate photoperiodic reproduction.

Animals adequately modulate their physiological status and behavior according to the season. Many animals sense photoperiod for seasonal adaptation, and the circadian clock is suggested to play an essential role in photoperiodic time measurement. However, circadian clock-driven neural signals in the brain that convey photoperiodic information remain unclear. Here, we focused on brain extracellular dynamics of a classical neurotransmitter glutamate, which is widely used for brain neurotransmission, and analyzed its involvement in photoperiodic responses using the bean bug Riptortus pedestris that shows clear photoperiodism in reproduction. Extracellular glutamate levels in the whole brain were significantly higher under short-day conditions, which cause a reproductive diapause, than those under long-day conditions. The photoperiodic change in glutamate levels was clearly abolished by knockdown of the clock gene period. We also demonstrated that genetic modulation of glutamate dynamics by knockdown of glutamate-metabolizing enzyme genes, glutamate oxaloacetate transaminase (got) and glutamine synthetase (gs), attenuated photoperiodic responses in reproduction. Further, we investigated glutamate-mediated photoperiodic modulations at a cellular level, focusing on the pars intercerebralis (PI) neurons that photoperiodically change their neural activity and promote oviposition. Electrophysiological analyses showed that L-Glutamate acts as an inhibitory signal to PI neurons via glutamate-gated chloride channel (GluCl). Additionally, combination of electrophysiology and genetics revealed that knockdown of got, gs, and glucl disrupted cellular photoperiodic responses of the PI neurons, in addition to reproductive phenotypes. Our results reveal that the extracellular glutamate dynamics are photoperiodically regulated depending on the clock gene and play an essential role in the photoperiodic control of reproduction via inhibitory pathways.

Possible involvement of NO-cGMP signaling in the antidepressant like Effect of Amantadine in mice.

In the present study, antidepressant like effect of amantadine was studied in mice using tail suspension test (TST) and forced swim test (FST). Further the effect of amantadine treatment on the brain nitrite, glutamate and serotonin levels was also determined. Amantadine (AMT) (50, 100 and 150mg/kg, i.p.) was administered to the mice and after 30min of administration the mice were subjected to TST and FST. It was observed that the administration of AMT (100 and 150mg/kg, i.p.) decreased the immobility period of mice in TST and FST significantly as compared to control. The findings from the whole brain neurochemical assay suggested that the AMT (100 and 150mg/kg, i.p.) treatment decreased the brain nitrite and glutamate level but increased the brain serotonin significantly as compared to control. Further the influence of NO-cGMP signaling in the antidepressant like effect of amantadine was also determined. It was observed that the NO donor (i.e. L-Arginine (50mg/kg, i.p.)) potentiated the effect elicited by AMT (50mg/kg, i.p.) in FST and decreased the brain serotonin level of AMT (50mg/kg, i.p.) treated mice. Further the pretreatment of cGMP modulator (i.e. Sildenafil (1mg/kg, i.p.)) potentiated the behavioral effect elicited by AMT (50mg/kg, i.p.) in TST and FST and decreased the brain nitrite and glutamate level of AMT (50mg/kg, i.p.) treated mice. In conclusion, amantadine exerted antidepressant like effect in mice and NO-cGMP signaling influences the antidepressant like effect of amantadine in mice.

Chronic Light-Distorted Glutamate-Cortisol Signaling, Behavioral and Histological Markers, and Induced Oxidative Stress and Dementia: An Amelioration by Melatonin

The present work aimed to investigate the induction of circadian rhythm dysfunction and dementia upon chronic exposure to light-light and its reversal by melatonin in Wistar rats. Animals underwent different light-dark conditions, viz., light/dark (LD), light/light (LL), and dark/dark (DD) in respective groups for 4 months. Melatonin 0.5 mg/kg s.c., dextromethorphan 50 μg/100 g s.c., and mifepristone 25 μg/100 g s.c. were given once a day. Chronic LL and DD conditions significantly increased brain glutamate and cortisol levels. The LL period caused a deficit in spatial memory, working memory, decision making, and exploration of novel objects, compared to LD animals. A significant (p < 0.05) change in neuropathological observations in the hippocampus, CA1, CA2, and CA3; cortex; and cerebellum regions (40×, 100×, and 400×) was observed in the histological study. Induced oxidative stress in brain tissue was also observed by estimating tissue glutathione and TBARS levels. Dextromethorphan (NMDA antagonist), mifepristone (corticosterone antagonist), and melatonin significantly (p < 0.05) reversed the pathological states caused due to LL. The histological features in the hippocampus, cortex, and cerebellum region revealed inflammatory cells, vacuolation, and pyknotic cells, which were significantly rescued by antagonizing NMDA or cortisol or melatonin treatment. It may be concluded that continuous exposure to light-light conditions produced an imbalance between neuronal excitation and stress hormone, leading to poor cognitive abilities and neuropathology.

Motor Cortex Excitation/Inhibition Imbalance in Young Adults With Autism Spectrum Disorder: A MRS-TMS Approach.

Excitatory/inhibitory imbalance has been suggested as a neurobiological substrate of the cognitive symptomatology in Autism Spectrum Disorder (ASD). Studies using magnetic resonance spectroscopy (MRS) attempted to characterize GABA and Glutamate brain levels in ASD. However mixed findings have been reported. Here, we characterize both neurochemical and physiological aspects of GABA system in ASD by implementing a more comprehensive approach combining MRS and transcranial magnetic stimulation (TMS). A group of 16 young ASD adults and a group of 17 controls participated in this study. We employed one MRS session to assess motor cortex GABA+ and Glutamate+Glutamine (Glx) levels using MEGAPRESS and PRESS sequences, respectively. Additionally, a TMS experiment was implemented including paired-pulse (SICI, ICF and LICI), input-output curve and cortical silent period to probe cortical excitability. Our results showed a significantly increased Glx, with unchanged GABA+ levels in the ASD group compared with controls. Single TMS measures did not differ between groups, although exploratory within-group analysis showed impaired inhibition in SICI5ms, in ASD. Importantly, we observed a correlation between GABA levels and measures of the input-output TMS recruitment curve (slope and MEP amplitude) in the control group but not in ASD, as further demonstrated by direct between group comparisons. In this exploratory study, we found evidence of increased Glx levels which may contribute to ASD excitatory/inhibitory imbalance while highlighting the relevance of conducting further larger-scale studies to investigate the GABA system from complementary perspectives, using both MRS and TMS techniques.

Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model.

Depression is a common and serious complication following traumatic brain injury (TBI). Both depression and TBI have independently been associated with pathologically elevated extracellular brain glutamate levels. In the setting of TBI, blood glutamate scavenging with pyruvate has been widely shown as an effective method to provide neuroprotection by reducing blood glutamate and subsequent brain glutamate levels. Here we evaluate pyruvate as a novel approach in the treatment and prevention of post-TBI depression-like behavior in a rat model. Rats were divided into five groups: (1) sham-operated control with pyruvate, (2) sham-operated control with placebo, (3) post-TBI with placebo, (4) post-TBI given preventative pyruvate, and (5) post-TBI treated with pyruvate. These groups had an equal number of females and males. Rats were assessed for depressive-like behavior, neurological status, and glutamate levels in the blood and brain. Post-TBI neurological deficits with concurrent elevations in glutamate levels were demonstrated, with peak glutamate levels 24 h after TBI. Following TBI, the administration of either prophylactic or therapeutic pyruvate led to reduced glutamate levels, improved neurologic recovery, and improved depressive-like behavior. Glutamate scavenging with pyruvate may be an effective prophylactic and therapeutic option for post-TBI depression by reducing associated elevations in brain glutamate levels.

Effects of sex hormones on brain GABA and glutamate levels in a cis- and transgender cohort

Sex hormones affect the GABAergic and glutamatergic neurotransmitter system as demonstrated in animal studies. However, human research has mostly been correlational in nature. Here, we aimed at substantiating causal interpretations of the interaction between sex hormones and neurotransmitter function by using magnetic resonance spectroscopy imaging (MRSI) to study the effect of gender-affirming hormone treatment (GHT) in transgender individuals.Fifteen trans men (TM) with a DSM-5 diagnosis of gender dysphoria, undergoing GHT, and 15 age-matched cisgender women (CW), receiving no therapy, underwent MRSI before and after at least 12 weeks. Additionally, sex differences in neurotransmitter levels were evaluated in an independent sample of 80 cisgender men and 79 cisgender women. Mean GABA+ (combination of GABA and macromolecules) and Glx (combination of glutamate and glutamine) ratios to total creatine (GABA+/tCr, Glx/tCr) were calculated in five predefined regions-of-interest (hippocampus, insula, pallidum, putamen and thalamus).Linear mixed models analysis revealed a significant measurement by gender identity effect (pcorr. = 0.048) for GABA+/tCr ratios in the hippocampus, with the TM cohort showing decreased GABA+/tCr levels after GHT compared to CW. Moreover, analysis of covariance showed a significant sex difference in insula GABA+/tCr ratios (pcorr. = 0.049), indicating elevated GABA levels in cisgender women compared to cisgender men.Our study demonstrates GHT treatment-induced GABA+/tCr reductions in the hippocampus, indicating hormone receptor activation on GABAergic cells and testosterone-induced neuroplastic processes within the hippocampus. Moreover, elevated GABA levels in the female compared to the male insula highlight the importance of including sex as factor in future MRS studies. Data availability statementDue to data protection laws processed data is available from the authors upon reasonable request. Please contact rupert.lanzenberger@meduniwien.ac.at with any questions or requests.

1H-[13C]-NMR investigation of brain energy metabolism in zebrafish: Impact of acute ethanol

Zebrafish has emerged as an excellent model organism for understanding the biology of the central nervous system. There is limited data pertaining to neurotransmitter energetics in the zebrafish brain. The present study evaluated brain energy metabolism in zebrafish by 1H-[13C]-NMR spectroscopy together with an intracardial administration of [1,6-13C2]glucose. Additionally, the impact of acute ethanol (1% in water) on brain energy metabolism was evaluated. The 13C turnover of brain amino acids from [1,6-13C2]glucose was measured in 1H-[13C]-NMR spectrum of brain tissue extract from 15 min to 90 min. The concentrations of neurometabolites in zebrafish are different than in rats and mice. There is fast incorporation of 13C labels into brain amino acids suggesting rapid glucose metabolism in the zebrafish brain. The incorporation of 13C in [4-13C]glutamate increased linearly until 30 min, and was maintained to a similar level thereafter. This is followed by [4-13C]glutamine and [3-13C]glutamate. The 13C turnover of [2–13C]GABA was much slower, and could attain ∼64% of [4-13C]glutamate labeling even at 90 min. Acute ethanol exposure significantly (p < 0.04) reduced levels of glutamate and NAA in the zebrafish brain. Most interestingly, the amount of 13C label accumulated into [4-13C]glutamate (p = 0.016), [2-13C]GABA (p = 0.016) and [3-13C]glutamate (p = 0.029) was decreased following acute neurotoxicity of ethanol. Moreover, the reduction in [4-13C]glutamine labeling in ethanol exposed fish points towards reduced synaptic transmission in acute ethanol exposed zebrafish. These data suggest that acute ethanol exposure in zebrafish suppresses neurometabolic activity of glutamatergic and GABAergic neurons. Zebrafish exhibited neurometabolism similar to rats, mice and humans, and could be used as an alternate model to study the mechanism of various neurological disorders, and drug screening.