Amino Acid Neurotransmitters Glutamate Research Articles

Impact of Perinatal Arsenic Exposure on Amino Acid Neurotransmitters and Bioenergetics Molecules in the Hippocampus of Rats

Developmental neurotoxicity of Arsenic (As) is a major concern worldwide. High level As exposure is associated with several chronic diseases including adverse pregnancy and birth outcomes. However, very a lack of information on its ability to impair neurodevelopment at lower exposure. To date, there are very few animal studies during the perinatal period of As exposure. Although exposure to As induces developmental neurotoxicity, there is a lack of data regarding its specific effects on amino acid neurotransmitters and bioenergetics biomolecules in the hippocampus of developing rats exposed to As during the perinatal period (GD6-PD21). In continuation of previous studies, rats were exposed to As from gestational day (GD 6) through PD 21 with targeted doses of 0, 2.0, and 4.0 mg/kg/day, respectively. HPLC-UV method was used to estimate the level of amino acid neurotransmitters (aspartate, glutamate, homocysteine, glutamine, serine, and glycine) and the level of Adenosine 5’-Triphosphate (ATP), Adenosine Diphosphate (ADP), Adenosine Monophosphate (AMP), Nicotinamide Mononucleotide (NMN), Nicotinamide Adenine Dinucleotide (NAD+), reduced Nicotinamide Adenine Dinucleotide (NADH) in the hippocampus of rats after the exposure of As. Amino acid neurotransmitter levels, a predictive biomarker of As-induced developmental neurotoxicity were found to be altered. ATP, ADP, and AMP were also significantly impaired in the hippocampus of As-exposed rats. We have observed that the hippocampus is susceptible to As toxicity, both because of the high energy depletion and the alterations in the levels of selected amino acid neurotransmitters. Taken together, our results indicate that perinatal As exposure appears to be critical and vulnerable.

Depression: magnetic resonance spectroscopy studies (review)

Magnetic resonance spectroscopy (MRS) is a non-invasive method for assessing the neurochemical state of the brain. In recent years, the growth in the number of high-field scanners has led to a rapid increase in such studies and improvement in the quality of MRS data, the development of mechanisms and technologies for obtaining and processing results.The review is devoted to the study of the possibilities of MRS in the study of brain neurochemistry in depression. The fundamentals of techniques and various approaches to MRS, technical requirements for the study material, advantages and disadvantages of the method, difficulties in interpreting the results, and prospects for combining MRS with fMRI and EEG are considered. Most spectroscopic studies performed in depression show an abnormal decrease in the concentrations of the amino acid neurotransmitters γ-aminobutyric acid and glutamate, which is consistent with the results of post-mortem histopathological studies. Multivariate studies are needed to determine the anatomical and clinical specificity of changes in Glx and GABA levels that are found in depressed patients.The presented material can be used and form the basis for further multimodal experiments using MRS, which may be relevant both for the informed development of more effective drugs, and last but not least, neurofeedback tools aimed at interactive interventions in the neural network organization in depressive disorders.

Ketamine as an adjunctive therapy for major depression - a randomised controlled pragmatic pilot trial (Karma-Dep Trial).

Background: Depression is a common psychiatric disorder that has become the leading cause of disability worldwide. The standard medical care for depression over the past 50 years has focused on monoamine neurotransmitters. These treatments can take weeks to take effect, highlighting the need for novel treatment strategies. One such approach may be ketamine. Ketamine acts as an antagonist of the N-methyl-D-asparate receptor and thus targets the excitatory amino acid neurotransmitter glutamate. Interestingly, at sub-anaesthetic doses, a single infusion of ketamine can elicit a rapid, though transient, antidepressant response. Methods: The aim of this study was to conduct a pragmatic randomised controlled pilot trial of four once-weekly ketamine infusions as an adjunctive therapy for depression. The main objective was to assess trial procedures to inform a future definitive trial. The primary clinical outcome was the 24-item Hamilton Rating Scale for Depression (HRSD-24). Trial participants were patients admitted to St Patrick's Mental Health Services for treatment of a depressive episode. They underwent usual inpatient care as prescribed by their treating team. Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up. Results: In total, 1581 admissions to St Patrick's Hospital were assessed for eligibility over nine months, with 125 (8%) meeting criteria, with 25 (20%) providing consent. In total, 13 were randomly assigned to the ketamine arm and 12 to the midazolam arm. There were no major differences in HRSD-24 scores between the two groups. The infusions were generally safe and well tolerated. Conclusions: This is the first pragmatic pilot trial of adjunctive serial ketamine infusions for hospitalised depression, an important possible use of ketamine. This study suggests that a definitive trial of adjunctive ketamine is feasible. Trial registration: ClinicalTrials.gov NCT03256162 21/08/2017; EudraCT 2016-004764-18 30/11/2016.

Ketamine as an adjunctive therapy for major depression - a randomised controlled pragmatic pilot trial (Karma-Dep Trial)

Background: Depression is a common psychiatric disorder that has become the leading cause of disability worldwide. The standard medical care for depression over the past 50 years has focused on monoamine neurotransmitters. These treatments can take weeks to take effect, highlighting the need for novel treatment strategies. One such approach may be ketamine. Ketamine acts as an antagonist of the N-methyl-D-asparate receptor and thus targets the excitatory amino acid neurotransmitter glutamate. Interestingly, at sub-anaesthetic doses, a single infusion of ketamine can elicit a rapid, though transient, antidepressant response. Methods: The aim of this study was to conduct a pragmatic randomised controlled pilot trial of four once-weekly ketamine infusions as an adjunctive therapy for depression. The main objective was to assess trial procedures to inform a future definitive trial. The primary clinical outcome was the 24-item Hamilton Rating Scale for Depression (HRSD-24). Trial participants were patients admitted to St Patrick’s Mental Health Services for treatment of a depressive episode. They underwent usual inpatient care as prescribed by their treating team. Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up. Results: In total, 1581 admissions to St Patrick’s Hospital were assessed for eligibility over nine months, with 125 (8%) meeting criteria, with 25 (20%) providing consent. In total, 13 were randomly assigned to the ketamine arm and 12 to the midazolam arm. There were no major differences in HRSD-24 scores between the two groups. The infusions were generally safe and well tolerated. Conclusions: This is the first pragmatic pilot trial of adjunctive serial ketamine infusions for hospitalised depression, an important possible use of ketamine. This study suggests that a definitive trial of adjunctive ketamine is feasible. Trial registration: ClinicalTrials.gov NCT03256162 21/08/2017; EudraCT 2016-004764-18 30/11/2016.

Ketamine as an adjunctive therapy for major depression - a randomised controlled pragmatic pilot trial (Karma-Dep Trial).

Background: Depression is a common psychiatric disorder that has become the leading cause of disability worldwide. The standard medical care for depression over the past 50 years has focused on monoamine neurotransmitters. These treatments can take weeks to take effect, highlighting the need for novel treatment strategies. One such approach may be ketamine. Ketamine acts as an antagonist of the N-methyl-D-asparate receptor and thus targets the excitatory amino acid neurotransmitter glutamate. Interestingly, at sub-anaesthetic doses, a single infusion of ketamine can elicit a rapid, though transient, antidepressant response. Methods: The aim of this study was to conduct a pragmatic randomised controlled pilot trial of four once-weekly ketamine infusions as an adjunctive therapy for depression. The main objective was to assess trial procedures to inform a future definitive trial. The primary clinical outcome was the 24-item Hamilton Rating Scale for Depression (HRSD-24). Trial participants were patients admitted to St Patrick's Mental Health Services for treatment of a depressive episode. They underwent usual inpatient care as prescribed by their treating team. Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up. Results: In total, 1581 admissions to St Patrick's Hospital were assessed for eligibility over nine months, with 125 (8%) meeting criteria, with 25 (20%) providing consent. In total, 13 were randomly assigned to the ketamine arm and 12 to the midazolam arm. There were no major differences in HRSD-24 scores between the two groups. The infusions were generally safe and well tolerated. Conclusions: This is the first pragmatic pilot trial of adjunctive serial ketamine infusions for hospitalised depression, an important possible use of ketamine. This study suggests that a definitive trial of adjunctive ketamine is feasible. Trial registration: ClinicalTrials.gov NCT03256162 21/08/2017; EudraCT 2016-004764-18 30/11/2016.

Stable cyclopropene-containing analogs of the amino acid neurotransmitter glutamate

As a neurotransmitter, the amino acid glutamate has been the subject of efforts to generate structural analogs with unique properties. Here we report a practical, half-gram synthesis of two cyclopropene-containing glutamate analogs. These analogs are stable in solution, in the presence of the biological nucleophile glutathione, upon concentration, and during long-term storage, while maintaining their amenability to photo- or enzyme-caging and reactivity with bioorthogonal reaction partners like s-tetrazine or light-activated tetrazoles.

Modeling of excitatory amino acid transporters and clearance of synaptic cleft on millisecond time scale

Excitatory Amino Acid Transporters (EAATs) operate over wide time scales in the brain. They maintain low ambient concentrations of the primary excitatory amino acid neurotransmitter glutamate, but they also seem to play a significant role in clearing glutamate from the synaptic cleft in the millisecond time-scale process of chemical communication that occurs between neurons. The detailed kinetic mechanisms underlying glutamate uptake and clearance remain incompletely understood. In this work we used a combination of methods to model EAAT kinetics and gain insight into the impact of transport on glutamate dynamics in a general sense. We derive reliable estimates of the turnover rates of the three major EAAT subtypes expressed in the mammalian cerebral cortex. Previous studies have provided transporter kinetic estimates that vary over an order of magnitude. The values obtained in this study are consistent with estimates that suggest the unitary transporter rates are approximately 20-fold slower than the time course of glutamate in the synapse. A combined diffusion/transport model provides a possible mechanism for the apparent discrepancy.

Molecular composition and heterogeneity of the LRRC8-containing swelling-activated osmolyte channels in primary rat astrocytes.

The volume-regulated anion channel (VRAC) is a swelling-activated chloride channel that is permeable to inorganic anions and a variety of small organic molecules. VRAC is formed via heteromerization of LRRC8 proteins, among which LRRC8A is essential, while LRRC8B/C/D/E serve as exchangeable complementary partners. We used an RNAi approach and radiotracer assays to explore which LRRC8 isoforms contribute to swelling-activated release of diverse organic osmolytes in rat astrocytes. Efflux of uncharged osmolytes (myo-inositol and taurine) was suppressed by deletion of LRRC8A or LRRC8D, but not by deletion of LRRC8C+LRRC8E. Conversely, release of charged osmolytes (d-aspartate) was strongly reduced by deletion of LRRC8A or LRRC8C+LRRC8E, but largely unaffected by downregulation of LRRC8D. Our findings point to the existence of multiple heteromeric VRACs in the same cell type: LRRC8A/D-containing heteromers appear to dominate release of uncharged osmolytes, while LRRC8A/C/E, with the additional contribution of LRRC8D, creates a conduit for movement of charged molecules. The volume-regulated anion channel (VRAC) is the ubiquitously expressed vertebrate Cl- /anion channel that is composed of proteins belonging to the LRRC8 family and activated by cell swelling. In the brain, VRAC contributes to physiological and pathological release of a variety of small organic molecules, including the amino acid neurotransmitters glutamate, aspartate and taurine. In the present work, we explored the role of all five LRRC8 family members in the release of organic osmolytes from primary rat astrocytes. Expression of LRRC8 proteins was modified using an RNAi approach, and amino acid fluxes via VRAC were quantified by radiotracer assays in cells challenged with hypoosmotic medium (30% reduction in osmolarity). Consistent with our prior work, knockdown of LRRC8A potently and equally suppressed the release of radiolabelled d-[14 C]aspartate and [3 H]taurine. Among other LRRC8 subunits, downregulation of LRRC8D strongly inhibited release of the uncharged osmolytes [3 H]taurine and myo-[3 H]inositol, without major impact on the simultaneously measured efflux of the charged d-[14 C]aspartate. In contrast, the release of d-[14 C]aspartate was preferentially sensitive to deletion of LRRC8C+LRRC8E, but unaffected by downregulation of LRRC8D. Finally, siRNA knockdown of LRRC8C+LRRC8D strongly inhibited the release of all osmolytes. Overall, our findings suggest the existence of at least two distinct heteromeric VRACs in astroglial cells. The LRRC8A/D-containing permeability pathway appears to dominate the release of uncharged osmolytes, while an alternative channel (or channels) is composed of LRRC8A/C/D/E and responsible for the loss of charged molecules.

Early Paradoxical Increase of Dopamine: A Neurochemical Study of Olfactory Bulb in Asymptomatic and Symptomatic MPTP Treated Monkeys.

Parkinson’s disease (PD) is a neurodegenerative disease with both motor and non-motor manifestations. Hyposmia is one of the early non-motor symptoms, which can precede motor symptoms by several years. The relationship between hyposmia and PD remains elusive. Olfactory bulb (OB) pathology shows an increased number of olfactory dopaminergic cells, protein aggregates and dysfunction of neurotransmitter systems. In this study we examined tissue levels of dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and their metabolites, of noradrenaline (NA) and of the amino acid neurotransmitters aspartate, glutamate, taurine and γ-aminobutyric acid in OBs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated Macaca fascicularis in different stages, including monkeys who were always asymptomatic, monkeys who recovered from mild parkinsonian signs, and monkeys with stable moderate or severe parkinsonism. DA was increased compared to controls, while neither NA and 5-HT nor the amino acid neurotransmitters were significantly changed. Furthermore, DA increased before stable motor deficits appear with +51% in asymptomatic and +96% in recovered monkeys. Unchanged DA metabolites suggest a special metabolic profile of the newly formed DA neurons. Significant correlation of homovanillic acid (HVA) with taurine single values within the four MPTP groups and of aspartate with taurine within the asymptomatic and recovered MPTP groups, but not within the controls suggest interactions in the OB between taurine and the DA system and taurine and the excitatory neurotransmitter triggered by MPTP. This first investigation of OB in various stages after MPTP administration suggests that the DA increase seems to be an early phenomenon, not requiring profound nigrostriatal neurodegeneration or PD symptoms.

HIV antiretroviral drug Efavirenz induces anxiety-like and depression-like behavior in rats: evaluation of neurotransmitter alterations in the striatum

Efavirenz (EFV) is an effective antiretroviral drug with a favorable pharmacokinetic profile and widely used in combination regimens to treat HIV infection. However, there are major concerns about the safety of this drug. Patients treated with EFV often experience neuropsychiatric adverse effects, which frequently lead to switching to alternative EFV-free regimens. The mechanisms involved in the central action of EFV are intrinsically unclear. Thus, this study aimed to investigate the effects of acute and subchronic (2 weeks) EFV administration in a series of behavioral tests for anxiety-like and depression-like behavior in healthy rats. We also evaluated the effect of EFV treatment in striatal concentrations of monoamine neurotransmitters (serotonin, dopamine and noradrenaline) and their metabolites and the amino acid neurotransmitters glutamate and GABA. Our results showed that acute treatment with EFV induced an anxiogenic-like effect, while sub-chronic treatment induced both anxiogenic-like and depressive-like behavior which was dose related.. Additionally, EFV treatment caused marked alterations in the striatal concentrations of monoamines and their metabolites (and turnover rates) and the amino acid neurotransmitters glutamate and GABA. These changes were influenced by treatment duration and dose. These findings add more evidence about the neuropsychiatric adverse effects of EFV and propose potential new mechanisms for the toxic action of this drug in the central nervous system.

A photocaged, cyclopropene-containing analog of the amino acid neurotransmitter glutamate

Substituted cyclopropenes serve as compact biorthogonal appendages that enable analysis of biomolecules in complex systems. Neurotransmitters, a chemically diverse group of biomolecules that control neuron excitation and inhibition, are not among the systems that have been studied using biorthogonal chemistry. Here we describe the synthesis of cyclopropene-containing analogs of the excitatory amino acid neurotransmitter glutamate starting from a Garner’s aldehyde-derived alkyne. The deprotected cyclopropene glutamate was stable in solution but decomposed upon concentration. Appending a light-cleavable group improved the stability of the cyclopropene while simultaneously caging the neurotransmitter. This strategy has the potential to permit deployment of cyclopropene-modified glutamate as a bioorthogonal probe of the neurotransmitter glutamate in vivo with spatiotemporal precision.

Volume-regulated anion channel--a frenemy within the brain.

The volume-regulated anion channel (VRAC) is a ubiquitously expressed yet highly enigmatic member of the superfamily of chloride/anion channels. It is activated by cellular swelling and mediates regulatory cell volume decrease in a majority of vertebrate cells, including those in the central nervous system (CNS). In the brain, besides its crucial role in cellular volume regulation, VRAC is thought to play a part in cell proliferation, apoptosis, migration, and release of physiologically active molecules. Although these roles are not exclusive to the CNS, the relative significance of VRAC in the brain is amplified by several unique aspects of its physiology. One important example is the contribution of VRAC to the release of the excitatory amino acid neurotransmitters glutamate and aspartate. This latter process is thought to have impact on both normal brain functioning (such as astrocyte-neuron signaling) and neuropathology (via promoting the excitotoxic death of neuronal cells in stroke and traumatic brain injury). In spite of much work in the field, the molecular nature of VRAC remained unknown until less than 2 years ago. Two pioneer publications identified VRAC as the heterohexamer formed by the leucine-rich repeat-containing 8 (LRRC8) proteins. These findings galvanized the field and are likely to result in dramatic revisions to our understanding of the place and role of VRAC in the brain, as well as other organs and tissues. The present review briefly recapitulates critical findings in the CNS and focuses on anticipated impact on the LRRC8 discovery on further progress in neuroscience research.

Assessment of Amino Acid Neurotransmitters in Rat Brain Microdialysis Samples by High-Performance Liquid Chromatography with Coulometric Detection

A simple method was developed for simultaneous determination of five amino acid neurotransmitters (taurine, glutamate, aspartate, glycine, and γ-aminobutyric acid) in brain microdialysates by high-performance liquid chromatography with coulometric detection. The microdialysates were derivatized with o-phthalaldehyde in 5 mM sodium sulfite and separated within 17 min using isocratic elution. Detection parameters for these transmitters were linearity (r2) > 0.999 over the concentration range from 0.1 to 15.00 µM (0.01–1.00 µM for GABA); reproducibility 2.88%–11.67% (relative standard deviation); the limits of detection 4.4–17.2 fmol; and recovery 86.66%–103.42%. This method was successfully applied to analyze these neurotransmitters in the brain. The changes of neurotransmitters were also investigated via local administration of potassium chloride and bicuculline, which was a γ-aminobutyric acid receptor antagonist. It was found that the developed method is more efficient as compared to previously reported methods in simultaneously determining five major neurotransmitters because it shows quick separation and sensitive detection, and is easy to operate. This method can be a practical choice for continuous monitoring of the amino acid neurotransmittersin vivo.

Role of calcium, glutamate and NMDA in major depression and therapeutic application.

Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-D-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX-13, NRX-1047, Ro25-6981, LY392098, LY341495, D-cycloserine, D-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-aminocyclopropanecarboxylic acid, all of which target this system, have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression.

Biogenic Amines and the Amino Acids GABA and Glutamate: Relationships with Pain and Depression.

Although it is well known that there is a high degree of comorbidity between chronic pain and mood and anxiety disorders, the mechanisms involved in these co-occurrences are not clear. It appears that numerous neurotransmitters and neuromodulators are involved, and this chapter focuses on the monoamine neurotransmitters noradrenaline, 5-hydroxytryptamine (5-HT, serotonin), and dopamine and the amino acid neurotransmitters GABA (γ-aminobutyric acid) and glutamate in chronic pain and depression. Numerous preclinical and clinical neurochemical, neuroanatomical, pharmacological and molecular biological studies as well as clinical pharmacological treatment investigations implicate noradrenaline, 5-HT and, to a lesser extent, dopamine in the etiology of pain and depression. Similarly, preclinical and clinical studies on GABAergic and glutamatergic mechanisms as well as reports on the actions of neuroactive steroids suggest that GABA and glutamate play an important role in the etiology of pain and depression and may contribute to comorbidity.

Ex vivo (1)H nuclear magnetic resonance spectroscopy reveals systematic alterations in cerebral metabolites as the key pathogenetic mechanism of bilirubin encephalopathy.

BackgroundBilirubin encephalopathy (BE) is a severe neurologic sequelae induced by hyperbilirubinemia in newborns. However, the pathogenetic mechanisms underlying the clinical syndromes of BE remain ambiguous. Ex vivo1H nuclear magnetic resonance (NMR) spectroscopy was used to measure changes in the concentrations of cerebral metabolites in various brain areas of newborn 9-day-old rats subjected to bilirubin to explore the related mechanisms of BE.ResultsWhen measured 0.5 hr after injection of bilirubin, levels of the amino acid neurotransmitters glutamate (Glu), glutamine (Gln), and γ-aminobutyric acid (GABA) in hippocampus and occipital cortex significantly decreased, by contrast, levels of aspartate (Asp) considerably increased. In the cerebellum, Glu and Gln levels significantly decreased, while GABA, and Asp levels showed no significant differences. In BE 24 hr rats, all of the metabolic changes observed returned to normal in the hippocampus and occipital cortex; however, levels of Glu, Gln, GABA, and glycine significantly increased in the cerebellum.ConclusionsThese metabolic changes for the neurotransmitters are mostly likely the result of a shift in the steady-state equilibrium of the Gln-Glu-GABA metabolic cycle between astrocytes and neurons, in a region-specific manner. Changes in energy metabolism and the tricarboxylic acid cycle may also be involved in the pathogenesis of BE.

Brain GABA and glutamate levels in workers of two ant species (Hymenoptera: Formicidae): Interspecific differences and effects of queen presence/absence

Presence of amino acid neurotransmitters gamma-aminobutyric acid (GABA) and glutamate (Glu) in ant brains was reported in very few studies. To learn more about factors influencing GABA and Glu levels in ant brains, we applied high-performance liquid chromatography to measure levels of these compounds in single brains of workers of 2 ant species, Myrmica ruginodis (subfamily Myrmicinae) and Formica polyctena (subfamily Formicinae) taken from queenright/queenless colony fragments and tested in dyadic aggression tests consisting of an encounter with a nestmate, an alien conspecific or a small cricket. Brain glutamate levels were higher than those of GABA in both tested species. Brain GABA levels (in μmol/brain) and GABA : Glu ratio were higher in M. ruginodis (a submissive species) than in F. polyctena (a dominant, aggressive species) in spite of smaller brain weight of M. ruginodis. Brain glutamate levels (in μmol/brain) did not differ between the tested species, which implies that glutamate concentration (in μmol/mg of brain tissue) was higher in M. ruginodis. Queen absence was associated with increased worker brain GABA levels in F. polyctena, but not in M. ruginodis. No significant effects of opponent type were discovered. As GABA agonists enhance friendly social behavior in rodents, we hypothesize that elevated brain GABA levels of orphaned workers of F. polyctena facilitate the adoption of a new queen. This is the first report providing information on GABA and glutamate levels in single ant brains and documenting the effects of queen presence/absence on brain levels of amino acid neurotransmitters in workers of social Hymenoptera.

Analysis of Glutamate, GABA, Noradrenaline, Dopamine, Serotonin, and Metabolites Using Microbore UHPLC with Electrochemical Detection

The applicability of microbore ultrahigh performance liquid chromatography (UHPLC) with electrochemical detection for offline analysis of a number of well-known neurotransmitters in less than 10 μL microdialysis fractions is described. Two methods are presented for the analysis of monoamine or amino acid neurotransmitters, using the same UHPLC instrument. Speed of analysis of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and the metabolites homovanillic acid (HVA), 5-hydroxyindole aceticacid (5-HIAA), and 3,4-dihydroxyphenylacetic acid (DOPAC) was predominated by the retention behavior of NA, the nonideal behavior of matrix components, and the loss in signal of 5-HT. This method was optimized to meet the requirements for detection sensitivity and minimizing the size of collected fractions, which determines temporal resolution in microdialysis. The amino acid neurotransmitters glutamate (Glu) and γ-aminobutyric acid (GABA) were analyzed after an automated derivatization procedure. Under optimized conditions, Glu was resolved from a number of early eluting system peaks, while the total runtime was decreased to 15 min by a 4-fold increase of the flow rate under UHPLC conditions. The detection limit for Glu and GABA was 10 nmol/L (15 fmol in 1.5 μL); the monoamine neurotransmitters had a detection limit between 32 and 83 pmol/L (0.16-0.42 fmol in 5 μL) in standard solutions. Using UHPLC, the analysis times varied from 15 min to less than 2 min depending on the complexity of the samples and the substances to be analyzed.

C.14.01 DEBATE: Managing inadequate response to initial antidepressant therapy: to switch or not to switch?

Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-d-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX-13, NRX-1047, Ro25-6981, LY392098, LY341495, d-cycloserine, d-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-aminocyclopropanecarboxylic acid, all of which target this system, have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression.

Glutamatergic and GABAergic innervation of GnRH neurons in the human hypothalamus

Event Abstract Back to Event Glutamatergic and GABAergic innervation of GnRH neurons in the human hypothalamus E. Hrabovszky1*, C. S. Molnár1, I. Kallo2, B. Borsay3, L. Sarkadi3, L. Herczeg3, M. Watanabe4 and Z. Liposits1, 2 1 Hungarian Academy of Sciences, Institute of Experimental Medicine, Hungary 2 Pázmány Péter Catholic University, Department of Neuroscience, Hungary 3 University of Debrecen, Department of Forensic Medicine, Hungary 4 Hokkaido University School of Medicine, Department of Anatomy, Japan Neurosecretory projections of gonadotropin-releasing hormone (GnRH) neurons to the hypophysial portal capillaries represent the final common output way of the hypothalamus in the neuroendocrine control of reproduction. GnRH neurons receive afferent input from a variety of neurotransmitter systems which are only partly characterized in the human. In the present study we used immunohistochemical approaches to address the contribution of the amino acid neurotransmitters GABA and glutamate to the afferent regulation of human GnRH neurons. According to previous findings in rodents where GABA represents the main neurotransmitter in the afferent control of GnRH neurons, we found that vesicular GABA transporter-immunoreactive GABAergic axons abundantly innervated the cell bodies and the dendrites of human GnRH neurons. While in rats, only glutamatergic axons of the VGLUT2 phenotype innervate GnRH neurons, in human samples we observed both VGLUT1- and VGLUT2 immunoreactive afferent contacts on GnRH neurons, with a preferential accumulation on GnRH dendrites. These morphological observations implicate the classic amino acid neurotransmitters GABA and glutamate in the afferent regulation of human GnRH neurons. As in rodents, GABA-ergic and glutamatergic afferents may have important contributions to metabolic-, sex steroid-, circadian- and stress signaling to the reproductive axis. Acknowledgements Supported by: OTKA K69127, T73002 and K83710; ETT 122/2009; FP7/2007-2013 (n° 245009) Keywords: Neuroendocrinology, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Neuroendocrinology Citation: Hrabovszky E, Molnár CS, Kallo I, Borsay B, Sarkadi L, Herczeg L, Watanabe M and Liposits Z (2011). Glutamatergic and GABAergic innervation of GnRH neurons in the human hypothalamus. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00141 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. E. Hrabovszky, Hungarian Academy of Sciences, Institute of Experimental Medicine, Budapest, Hungary, hrabovszky.erik@koki.mta.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers E. Hrabovszky C. S Molnár I. Kallo B. Borsay L. Sarkadi L. Herczeg M. Watanabe Z. Liposits Google E. Hrabovszky C. S Molnár I. Kallo B. Borsay L. Sarkadi L. Herczeg M. Watanabe Z. Liposits Google Scholar E. Hrabovszky C. S Molnár I. Kallo B. Borsay L. Sarkadi L. Herczeg M. Watanabe Z. Liposits PubMed E. Hrabovszky C. S Molnár I. Kallo B. Borsay L. Sarkadi L. Herczeg M. Watanabe Z. Liposits Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.