The Experts below are selected from a list of 7326 Experts worldwide ranked by ideXlab platform
Gerard Sanacora - One of the best experts on this subject based on the ideXlab platform.
-
a new generation of antidepressants an update on the pharmaceutical pipeline for novel and rapid acting therapeutics in mood disorders based on glutamate gaba Neurotransmitter systems
Drug Discovery Today, 2019Co-Authors: Samuel T Wilkinson, Gerard SanacoraAbstract:Mood disorders represent the largest cause of disability worldwide. The monoaminergic deficiency hypothesis, which has dominated the conceptual framework for researching the pathophysiology of mood disorders and the development of novel treatment strategies, cannot fully explain the underlying neurobiology of mood disorders. Mounting evidence collected over the past two decades suggests the Amino Acid Neurotransmitter systems (glutamate and GABA) serve central roles in the pathophysiology of mood disorders. Here, we review progress in the development of compounds that act on these systems as well as their purported mechanisms of action. We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217.
-
1h 13c nuclear magnetic resonance spectroscopy measures of ketamine s effect on Amino Acid Neurotransmitter metabolism
Biological Psychiatry, 2012Co-Authors: Golam M I Chowdhury, Kevin L Behar, William Cho, Monique A Thomas, Douglas L Rothman, Gerard SanacoraAbstract:Ketamine has recently gained significant attention owing to its psychotomimetic and more recently discovered rapid antidepressant-like properties. 1 H-[ 13 C]-nuclear magnetic resonance studies were employed to explore potential physiological processes underlying these unique effects. [1- 13 C]glucose and [2- 13 C]acetate-nuclear magnetic resonance ex vivo studies were performed on the medial prefrontal cortex (mPFC) and hippocampus of rats acutely treated with 30 mg/kg or 80 mg/kg ketamine and compared with saline-treated animals to determine the effects of ketamine on Amino Acid Neurotransmitter cycling and glial metabolism. A subanesthetic, but not anesthetic, dose of ketamine significantly increased the percentage of 13 C-enrichments of glutamate, γ-Aminobutyric Acid, and glutamine in the mPFC of rats. Subanesthetic doses of ketamine increased mPFC Amino Acid Neurotransmitter cycling, as well as neuronal and glial energy metabolism. These data add to previous reports suggesting increased mPFC levels of glutamate release, following the administration of subanesthetic doses of ketamine, are related to the drug's acute effects on cognition, perception, and mood.
-
the antidepressant effect of ketamine is not associated with changes in occipital Amino Acid Neurotransmitter content as measured by 1h mrs
Psychiatry Research-neuroimaging, 2011Co-Authors: Gerald W Valentine, Graeme F Mason, Rosane Gomez, Madonna K Fasula, June Watzl, Brian Pittman, John H Krystal, Gerard SanacoraAbstract:Abstract The NMDA receptor antagonist ketamine can induce a rapid improvement in depressive symptoms that often endures for days after a single intravenous dose. The pharmacodynamic basis for this effect is poorly understood. Using a proton magnetic resonance spectroscopy ([ 1 H]-MRS) method that previously detected a normalization of Amino Acid Neurotransmitter (AANt) content after chronic treatment with conventional antidepressant treatments, we examined whether the acute action of ketamine is associated with alterations in AANt content as well. Ten subjects with major depressive disorder (MDD) received saline, then ketamine in a fixed order, one week apart, under single-blind conditions. Each infusion was associated with three [ 1 H] MRS scans (baseline, 3 h and 48 h post-infusion) that measured glutamate, GABA and glutamine within the occipital cortex. Rating scales were administered before, during and after each infusion. The rapid (1 h) and sustained (at least 7 days) antidepressant effect we observed after ketamine infusion was not associated with either baseline measures of, or changes in, occipital AANt content. Dissociative symptoms were not correlated with changes in depression scores. While our results indicate that changes in occipital AANt content are not a correlate of ketamine's antidepressant action, this may only apply to the regional and temporal windows of our MRS measurements.
R F Suckow - One of the best experts on this subject based on the ideXlab platform.
-
a pilot in vivo proton magnetic resonance spectroscopy study of Amino Acid Neurotransmitter response to ketamine treatment of major depressive disorder
Molecular Psychiatry, 2016Co-Authors: Matthew S Milak, C J Proper, S T Mulhern, A L Parter, Lawrence S Kegeles, R T Ogden, Carolyn I Rodriguez, Maria A Oquendo, R F Suckow, Thomas B CooperAbstract:The NMDA receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine’s antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate + glutamine (Glx) and γ-Aminobutyric Acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg/kg i.v.) was administered to eleven depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total ≤ 10) within 230 minutes of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 minutes. Mean areas under the curve (AUC) for Glx/W (p = 0.025) and GABA/W (p = 0.005) increased and correlated (r = 0.796; p=0.018). Clinical improvement correlated with 90-minute norketamine concentration (df=6, r=−0.78, p=0.023), but no other measures. Rapid increases in Glx and GABA in MDD following ketamine administration support the postulated antidepressant role of glutamate and for the first time raises the question of GABA’s role in the antidepressant action of ketamine. These data support the hypothesis1 that ketamine administration may cause an initial increase in glutamate that potentially activates mammalian target of rapamycin (mTOR) pathway via AMPA receptors, since ketamine blocks NMDA receptors. The role of the contemporaneous surge in GABA remains to be determined.2
-
A pilot in vivo proton magnetic resonance spectroscopy study of Amino Acid Neurotransmitter response to ketamine treatment of major depressive disorder
Molecular Psychiatry, 2016Co-Authors: Matthew S Milak, C J Proper, S T Mulhern, A L Parter, Lawrence S Kegeles, R T Ogden, Carolyn I Rodriguez, Maria A Oquendo, X Mao, R F SuckowAbstract:The N-methyl-D-aspartate receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine’s antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate+glutamine (Glx) and γ-Aminobutyric Acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg kg^−1 intravenously) was administered to 11 depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total score ⩽10) within 230 min of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 min. Mean areas under the curve for Glx/W ( P =0.025) and GABA/W ( P =0.005) increased and correlated ( r =0.796; P =0.018). Clinical improvement correlated with 90-min norketamine concentration (df=6, r =−0.78, P =0.023), but no other measures.
Sid Gilman - One of the best experts on this subject based on the ideXlab platform.
-
Journal of Chemical Neuroanatomy, Vol. 4:429-437 (1991) Excitatory and Inhibitory Amino Acid Neurotransmitter Binding Sites in the Cerebellar Cortex of the Pigeon
2016Co-Authors: Columba Livia, Roger L Albin, Sharin Y Sakurai, Richard L Makowiec, Sid GilmanAbstract:We used receptor autoradiography to determine the distribution of excitatory and inhibitory Amino Acid Neurotransmitter binding sites in the cerebellar cortex of the pigeon (Columba livia), ct-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid, kainate and metabotropic binding sites had highest levels in the molecular layer. N-methyl-t)-aspartate binding sites, assayed with both [3H]glutamate under selective conditions and with [3H]glycine binding to the associated strychnine-insensitive glycine site, had highest levels in the granule cell layer. There was little specific binding of the non-competitive N-methyl-D-aspartate antagonist, [3H]MK-801. The level of gamma-Aminobutyric Acid (GABA)-A binding sites was higher than GABA-B binding sites in both molecular and granule cell layers with the highest level of GABA-A sites in the granule cell layer. The highest level of GABA-B binding sites was in the molecular layer. [3H]Flunitrazepam binding levels were approximately the same in both molecular and granule cell layers. With the exception of kainate binding sites, the distribution of binding sites was identical to that seen in the cerebellar cortex of mammals. Our results support he concept that the chemoarchitecture of the cerebellar cortex has been conserved in the course of vertebrate evolution. KEY WORDS: Glutamate Gamma-Aminobutyric Acid Cerebellum Avian Evolutio
-
inhibitory and excitatory Amino Acid Neurotransmitter binding sites in cynomolgus monkey macaca fascicularis cervical spinal cord
Brain Research, 1993Co-Authors: Roger L Albin, Zane R Hollingsworth, Sharin Y Sakurai, Sid GilmanAbstract:Autoradiography of inhibitory and excitatory Amino Acid Neurotransmitter binding sites in the cervical spinal cord of M. fascicularis spinal cord revealed inhomogeneous distribution of all binding sites in spinal gray matter. Quisqualate-sensitive [3H]glutamate binding, [3H]MK-801 binding, benzodiazepine binding, kainate binding, and GABAB binding had highest levels in the superficial layers of the dorsal horn (laminae 1 and 2) and substantially lower levels in other laminae. [3H]Strychnine binding was more uniformly distributed throughout all laminae with highest levels in the superficial layers of the dorsal horn. These results are similar to those found in other mammals.
-
excitatory and inhibitory Amino Acid Neurotransmitter binding sites in the cerebellar cortex of the pigeon columba livia
Journal of Chemical Neuroanatomy, 1991Co-Authors: Roger L Albin, Sharin Y Sakurai, Richard L Makowiec, Sid GilmanAbstract:We used receptor autoradiography to determine the distribution of excitatory and inhibitory Amino Acid Neurotransmitter binding sites in the cerebellar cortex of the pigeon (Columba livia), ct-Amino-3hydroxy-5-methylisoxazole-4-propionic Acid, kainate and metabotropic binding sites had highest levels in the molecular layer. N-methyl-t)-aspartate binding sites, assayed with both [3H]glutamate under selective conditions and with [3H]glycine binding to the associated strychnine-insensitive glycine site, had highest levels in the granule cell layer. There was little specific binding of the non-competitive N-methyl-D-aspartate antagonist, [3H]MK-801. The level of gamma-Aminobutyric Acid (GABA)-A binding sites was higher than GABA-B binding sites in both molecular and granule cell layers with the highest level of GABA-A sites in the granule cell layer. The highest level of GABA-B binding sites was in the molecular layer. [3H]Flunitrazepam binding levels were approximately the same in both molecular and granule cell layers. With the exception of kainate binding sites, the distribution of binding sites was identical to that seen in the cerebellar cortex of mammals. Our results support the concept that the chemoarchitecture of the cerebellar cortex has been conserved in the course of vertebrate evolution.
Matthew S Milak - One of the best experts on this subject based on the ideXlab platform.
-
a pilot in vivo proton magnetic resonance spectroscopy study of Amino Acid Neurotransmitter response to ketamine treatment of major depressive disorder
Molecular Psychiatry, 2016Co-Authors: Matthew S Milak, C J Proper, S T Mulhern, A L Parter, Lawrence S Kegeles, R T Ogden, Carolyn I Rodriguez, Maria A Oquendo, R F Suckow, Thomas B CooperAbstract:The NMDA receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine’s antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate + glutamine (Glx) and γ-Aminobutyric Acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg/kg i.v.) was administered to eleven depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total ≤ 10) within 230 minutes of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 minutes. Mean areas under the curve (AUC) for Glx/W (p = 0.025) and GABA/W (p = 0.005) increased and correlated (r = 0.796; p=0.018). Clinical improvement correlated with 90-minute norketamine concentration (df=6, r=−0.78, p=0.023), but no other measures. Rapid increases in Glx and GABA in MDD following ketamine administration support the postulated antidepressant role of glutamate and for the first time raises the question of GABA’s role in the antidepressant action of ketamine. These data support the hypothesis1 that ketamine administration may cause an initial increase in glutamate that potentially activates mammalian target of rapamycin (mTOR) pathway via AMPA receptors, since ketamine blocks NMDA receptors. The role of the contemporaneous surge in GABA remains to be determined.2
-
A pilot in vivo proton magnetic resonance spectroscopy study of Amino Acid Neurotransmitter response to ketamine treatment of major depressive disorder
Molecular Psychiatry, 2016Co-Authors: Matthew S Milak, C J Proper, S T Mulhern, A L Parter, Lawrence S Kegeles, R T Ogden, Carolyn I Rodriguez, Maria A Oquendo, X Mao, R F SuckowAbstract:The N-methyl-D-aspartate receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine’s antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate+glutamine (Glx) and γ-Aminobutyric Acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg kg^−1 intravenously) was administered to 11 depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total score ⩽10) within 230 min of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 min. Mean areas under the curve for Glx/W ( P =0.025) and GABA/W ( P =0.005) increased and correlated ( r =0.796; P =0.018). Clinical improvement correlated with 90-min norketamine concentration (df=6, r =−0.78, P =0.023), but no other measures.
Ursula Sonnewald - One of the best experts on this subject based on the ideXlab platform.
-
energy and Amino Acid Neurotransmitter metabolism in astrocytes
The Biomedical & Life Sciences Collection, 2009Co-Authors: Helle S Waagepetersen, Ursula Sonnewald, Arne SchousboeAbstract:Kno wledge about the functional roles of astrocytes has developed enormously over the past 30 years and it is interesting to note that even a century ago Ramon y Cajal (1911) was concerned that it would take a long time until it could be elucidated how important astrocytes would be in maintaining basic elements of brain function. By now it is clear that astrocytes are of pivotal importance for ion homeostasis, inter-cellular communication, exchange of metabolites, and clearance of the extrasynap-tic milieu of the Neurotransmitters glutamate and gamma-Aminobutyric Acid (GABA)
-
new aspects of Amino Acid Neurotransmitter synthesis in cultured neurons
Journal of Neurochemistry, 2008Co-Authors: Ursula Sonnewald, Helle S Waagepetersen, Arne SchousboeAbstract:The synthesis and degradation of GABA, glutamate and aspartate, has been studied extensively, both in vivo and in vitro. Cell culture studies have shown that metabolism of these Amino Acids is compartmentalized (Qu et al. 2000; Waagepetersen et al. 1998). By magnetic resonance spectroscopy (MRS) analysis of 13C incorporation into different positions in cerebral metabolites, information has been obtained giving strong support to the concept of intracellular heterogeneity in different brain cell cultures. It has been suggested that compartmentalisation of metabolism also exists at the mitochondrial level (Sonnewald et al. 1998). It was shown that metabolism and uptake of glutamate in cerebellar granule neurons was differentially affected by thiopental (Qu et al. 2000). TCA cycle activity in cortical neurons has been shown to be associated with multiple compartments as well (Waagepetersen et al. 1998). Cycling ratios calculated from MRS data obtained from cell extracts, showed a significant effect of depolarization on the ratio of glutamate but not on that of GABA. An observation that indicates multiple TCA cycles as well, in this case with regard to synthesis of glutamate and GABA. A growing amount of evidence seems to point strongly towards intracellular compartmentalisation of Neurotransmitter Amino Acid metabolism in individual cells. References Qu H. et al. (2000) Neurochem. Int. 37, 207–215. Waagepetersen H. et al. (1998) JCBFM18, 109–117. Sonnewald U. et al. (1998) JCBFM18, 231–237.
-
distinct changes in neuronal and astrocytic Amino Acid Neurotransmitter metabolism in mice with reduced numbers of synaptic vesicles
Journal of Neurochemistry, 2008Co-Authors: Inger Lise Bogen, Ursula Sonnewald, Oystein Risa, Kristin Huse Haug, Frode Fonnum, Ivar S WalaasAbstract:The relations between glutamate and GABA concentrations and synaptic vesicle density in nerve terminals were examined in an animal model with 40–50% reduction in synaptic vesicle numbers caused by inactivation of the genes encoding synapsin I and II. Concentrations and synthesis of Amino Acids were measured in extracts from cerebrum and a crude synaptosomal fraction by HPLC and 13C nuclear magnetic resonance spectroscopy (NMRS), respectively. Analysis of cerebrum extracts, comprising both Neurotransmitter and metabolic pools, showed decreased concentration of GABA, increased concentration of glutamine and unchanged concentration of glutamate in synapsin I and II double knockout (DKO) mice. In contrast, both glutamate and GABA concentrations were decreased in crude synaptosomes isolated from synapsin DKO mice, suggesting that the large metabolic pool of glutamate in the cerebral extracts may overshadow minor changes in the transmitter pool. 13C NMRS studies showed that the changes in Amino Acid concentrations in the synapsin DKO mice were caused by decreased synthesis of GABA (20–24%) in cerebral neurons and increased synthesis of glutamine (36%) in astrocytes. In a crude synaptosomal fraction, the glutamate synthesis was reduced (24%), but this reduction could not be detected in cerebrum extracts. We suggest that lack of synaptic vesicles causes down-regulation of neuronal GABA and glutamate synthesis, with a concomitant increase in astrocytic synthesis of glutamine, in order to maintain normal Neurotransmitter concentrations in the nerve terminal cytosol.
-
Amino Acid Neurotransmitter metabolism in neurones and glia following kainate injection in rats
Neuroscience Letters, 2000Co-Authors: Bernd Muller, Mari Garseth, Linda R White, Jan O Aasly, Ursula SonnewaldAbstract:Abstract Limbic seizure was induced in rats by intraperitoneal injection of the glutamate receptor agonist kainic Acid. After 14 days [1– 13 C]glucose and [1,2– 13 C]acetate were injected subcutaneously and the rats killed 15 min later. Analysis of brain extracts was performed using 13 C-magnetic resonance spectroscopy and high performance liquid chromatography. No significant differences between the two groups of rats were found for label concentration in blood or total metabolite tissue levels. Only astrocytes are able to utilize acetate as a substrate, whereas glucose is thought to be metabolized predominantly in the neuronal tricarboxylic Acid cycle. Thus information about neuronal and astrocytic metabolism could be obtained in the same animal. A significant increase in label derived from [1– 13 C]glucose was observed in metabolites such as glutamate, γ-Aminobutyric Acid, aspartate, and succinate (all of which are mainly labelled in neurones). The increased labelling of glutamine in epileptic rats might be due to transfer of labelled glutamate from neurones to astrocytes. Astrocytic metabolism of acetate and transfer of glutamine to neurones were not affected. The results suggest that increased neuronal activity 2 weeks following epileptic seizures produces increased Amino Acid turnover in neurones. Changes in astrocytic metabolism were not detected.
-
release of α ketoglutarate malate and succinate from cultured astrocytes possible role in Amino Acid Neurotransmitter homeostasis
Neuroscience Letters, 1994Co-Authors: Niels Westergaard, Ursula Sonnewald, Arne SchousboeAbstract:The rates of release of the tricarboxylic Acid (TCA) cycle constituents alpha-ketoglutarate (alpha-KG), malate and succinate were determined in cultured mouse cerebellar astrocytes, cerebellar granule neurons and cerebral cortical neurons. In addition, its dependence on the external HCO3- concentration was investigated together with effects of K+, glutamate and glutamine. The rate of release of these TCA cycle constituents was linear with time for at least 48 h regardless of the cell type. The release was for all 3 compounds much higher in the astrocytes (13.1, 3.8 and 1.5 nmol.h-1.mg-1 for alpha-KG, malate and succinate, respectively) than in cerebellar (6.5 and 1.5 for alpha-KG and malate) and cortical (3.5 and 1.2 for alpha-KG and malate) neurons. Release of succinate in the neurons could not be determined accurately due to the sensitivity of the assay. In the astrocytes the release of alpha-KG and malate was dependent on HCO3- in a saturable manner with Km values around 6 and 1 mM for alpha-KG and malate, respectively. The release of alpha-KG and malate from astrocytes was stimulated by glutamate (0.5 mM) whereas K+ (15 and 55 mM) and glutamine (0.5 mM) had no effect. The results clearly demonstrate that astrocytes but not neurons release appreciable amounts of TCA cycle intermediates reflecting the presence of pyruvate carboxylase in these cells. The exact functional importance of this release remains to be established but it could play some albeit a minor quantitative role for neuronal homeostasis of the Neurotransmitter Amino Acids glutamate and GABA.