Glutamate And Γ-aminobutyric Acid Research Articles

Evidence for release of glutamic acid, aspartic acid and substance P but not γ-aminobutyric acid from primary afferent fibres in rat spinal cord

In vitro superfusion release experiments and autoradiography were carried out on spinal cords of neonatally capsaicin-treated rats. Electrical and chemical stimulations significantly increased the release of aspartate, glutamate and γ-aminobutyric acid (GABA) from hemisected dorsal horn slices of vehicle-treated animals. In capsaicin-treated rats, the evoked release of aspartate, glutamate and substance P but not GABA, were significantly lower. Capsaicin (1 μM) stimulated the release of aspartate and glutamate, as reported for substance P. in control slices but this effect was not as apparent in tissues from capsaicin-treated rats. Evoked GABA release was not affected in either case. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, dizocilpine and GABA B binding sites were highly localised in the substantia gelatinosa. Capsaicin treatment did not affect the affinity of the binding sites in all four cases but significantly reduced the density of kainate, dizocilpine and GABA B binding sites. The data suggest that capsaicin-sensitive primary afferent fibres release aspartate, glutamate and Substance P following high-intensity stimulations and that this release might be modulated by presynaptic glutamate and GABA B receptors present on these terminals.

Cerebrospinal fluid concentrations of glutamate and GABA during perinatal cerebral hypoxia-ischemia and seizures

Cerebrospinal fluid (CSF) concentrations of glutamate and γ-aminobutyric acid (GABA), as estimates of levels in the extracellular compartment of brain, were determined in 7-day postnatal rats at the terminus of hypoxia-ischemia and during status epilepticus, induced with bicuculline, at 2 and 24 h of recovery. Hypoxia-ischemia was associated with increased CSF glutamate, which was not increased further during status epilepticus. In contrast, CSF GABA was increased by hypoxia-ischemia as well as by status epilepticus during recovery. CSF glutamate/GABA ratios in rat pups subjected to status epilepticus with or without prior hypoxia-ischemia were lower than control animals during recovery. The lack of any significant increase in glutamate or in the glutamate/GABA ratio during status epilepticus would preclude any neuronal injury from occurring in those immature rats sustaining seizures alone or any accentuation of brain damage in those animals subjected to prior cerebral hypoxia-ischemia.

Desyl Esters of Amino Acid Neurotransmitters. Phototriggers for Biologically Active Neurotransmitters

The application of the desyl or 2-oxo-1,2-diphenylethyl moiety as a photolabile ligand for the release of phosphates such as cAMP and inorganic phosphate (Pi)1,2 is extended to include selected excitatory amino acids. The synthesis and photochemical studies of N- and O-desyl-caged versions of the endogenous amino acid neurotransmitters glutamate and γ-aminobutyric acid (GABA) are reported. Photolysis at 350 nm of solutions of γ-O-desyl glutamate (11) and O-desyl GABA (14) in 1:1 H2O−acetonitrile cleanly produced free glutamate and GABA, respectively, with rate constants of ca. 107 s-1; 2-phenylbenzo[b]furan (2) was the only photobyproduct detected by HPLC. Photolysis quantum efficiencies for the disappearance of O-desyl amino acid esters were in the range of 0.29−0.31, and the appearance efficiencies of furan 2 (and the corresponding amino acid) were 0.14. The photolysis of 14 was efficiently quenched with sodium 2-naphthalenesulfonate, yielding a triplet lifetime of ca. 10 ns. Photolysis of 11 in mammali...

Effect of local cholecystokinin-8 administration on extracellular levels of amino acids and glycolytic products monitored by in vivo microdialysis in the fronto-parietal cortex of the rat

The effects of local cholecystokinin-8 (CCK-8) administration on cortical extracellular levels of amino acids, catecholamines and metabolism products were studied in the halothane anaesthetized rat by in vivo microdialysis. CCK-8 (10μM), administrated via a microdialysis probe, produced a significant increase in the levels of aspartate, glutamate and γ-aminobutyric acid (GABA), but not of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), lactate and pyruvate, which were simultaneously monitored. The increase in aspartate and glutamate levels produced by CCK-8 was about 3–4-fold. The effect of CCK-8 on aspartate levels was significantly inhibited by the CCKB antagonist, L-365,260 (20 mg kg −1, s.c.), but not by the CCKA antagonist, L-364,718 (20 mg kg −1 s.c.). In contrast, the increase in glutamate levels was inhibited by both L-365,260 and L-364,718. GABA was slightly, but significantly increased (∼30%), by local CCK-8 and was inhibited by both CCK antagonists. The present results show that CCK-8 exerts a strong modulatory action on both aspartate and glutamate release in rat cortex. While the effect of CCK-8 on aspartate is selectively mediated via CCKB receptor subtype, the effect of CCK-8 on glutamate appears to be mediated via both CCK A and CCK B receptor subtypes.

Oxytocin and vasopressin release in the olfactory bulb of parturient ewes: changes with maternal experience and effects on acetylcholine, γ-aminobutyric acid, glutamate and noradrenaline release

Maternal behaviour and the ewe's ability to recognize her lamb depend on olfactory cues and parturition, and are facilitated by maternal experience. Parturition induces a variety of neurochemical changes in the brain and, in particular, oxytocin (OT) release. This peptide injected centrally induces maternal behaviour. Oxytocin release occurs in the olfactory bulb (OB) at parturition and yet this structure is involved in the process of selective bonding with lamb. The present study therefore investigated the possibility that oxytocin release in the OB might modulate the release of classical transmitters that are known to be important in controlling selective recognition and whether maternal experience has any effect on this. We have first used in vivo microdialysis to measure OT release, as well as that of the related peptide, arginine-vasopressin (AVP), in the OB of maternally experienced and inexperienced ewes during parturition. While OT release significantly increased in both primiparous and multiparous ewes at parturition this increase was significantly greater in multiparous ewes. No significant change of AVP release was observed in either group. However, vagino-cervical stimulation (VCS) performed at 6 h post-partum caused similar increases in OT but not AVP release in both primiparous and multiparous ewes suggesting that the first birth experience potentiates the ability of VCS to evoke OT release within 6 h of parturition. Using retrodialysis, either OT (10 μM) or AVP (10 μM) were infused into the OB of multiparous and nulliparous ewes and their effects on modulating acetylcholine (ACh), noradrenaline (NA), glutamate and γ-aminobutyric acid (GABA) release were monitored. Both peptides produced an increase of ACh and NA in multiparous animals and this effect was either absent or less pronounced in nulliparous animals. OT, but not AVP, also increased GABA release equivalently in nulliparous and multiparous animals. Glutamate release was not altered in response to OT or AVP infusion. These results suggest that OT release in the OB at parturition may facilitate the recognition of lamb odours by modulating NA, ACh and GABA release which are of primary importance for olfactory memory. The reduced release of OT in the OB of primiparous ewes at parturition, together with its reduced ability to modulate NA and ACh release, might also partly explain why maternally inexperienced animals require a longer period to selectively bond with their lambs.

Distribution of glutamate- and GABA-immunoreactive neurons projecting to the cardioacceleratory center of the intermediolateral nucleus of the thoracic cord of SHR and WKY rats: a double-labeling study

We aimed at (1) determining the distribution of glutamate (Glu)- and γ-aminobutyric acid (GABA)-containing neurons in the brainstem with projections to the cardioacceleratory sympathetic preganglionic neurons in the intermediolateral nucleus (IML) of the upper thoracic cord and (2) determining whether such afferent projections in spontaneously hypertensive rats (SHR) differ from those of control Wistar-Kyoto (WKY) rats. We used a combination of electrophysiological methods to determine the site of HRP injection in the spinal cord and double-labeling methods for plotting the distribution of Glu- and GABA-immunoreactive neurons with projections to this site. HRP/Glu-labeled neurons (possibly glutamatergic) and HRP/GABA-labeled neurons (possibly GABAergic) were detected in 27% and 7% of the total HRP-labeled neurons of the central autonomic nuclei of 3 SHR rats and 3 WKY rats. HRP/Glu-labeled neurons were distributed predominantly ipsilaterally in 20 nuclei of the medulla oblongata, pons and hypothalamus, while HRP/GABA-labeled neurons were distributed in 7 nuclei of the medulla oblongata. No significant differences were found between the average percentages of HRP/Glu-labeled and HRP/GABA-labeled neurons in SHR and WKY rats. These findings indicate that: (1) the Glu-containing neurons represent a greater proportion than the GABA-containing neurons, (2) the proportions of these neurons appear to be similar in WKY and SHR rats and (3) generation of inbred tachycardia and hypertension in SHR rats can not be attributed to the topological and quantitative differences in the distribution of the glutamatergic and GABAergic neurons in the central autonomic nuclei.

Effects of taurine on depolarization-evoked release of amino acids from rat cortical synaptosomes

Effects of taurine on endogenous aspartic acid (Asp), glutamic acid (Glu) and γ-aminobutyric acid (GABA) release has been investigated using synaptosomes prepared from rat cerebral cortex. Although basal release of these amino acids was not affected, taurine inhibited KCl (30 mM)-evoked overflow of Asp, Glu and GABA in a concentration-dependent manner with potencies (IC 50) of 1 μM, 0.8 μM and 5 nM, respectively. Taurine (10 μM) maximally inhibited K +-evoked Asp, Glu and GABA overflow by 28, 37 and 65%, respectively. Phaclofen (10 μM, a GABA B receptor antagonist), but not bicuculline (10 μM, a GABA A receptor antagonist), counteracted the inhibition of GABA overflow, although the inhibition of Asp and Glu overflow was not attenuated. These data suggest that taurine may inhibit GABA release through the activation of presynaptic GABA B autoreceptors and, at high concentration, also act on Asp- and Glu-nerve terminals to regulate release of excitatory amino acids in rat cortex.

Glutamatergic and GABAergic synaptic currents in ganglion cells from isolated retinae of pigmented rats during postnatal development

This study was aimed at characterizing the earliest phases of synaptogenesis in the mammalian retina. Spontaneous activity of ganglion cells in the isolated superfused retina was used as an indicator for the functionality of synaptic connections. Retinal ganglion neurons (RGNs) were identified by location of their somata in the ganglion cell layer (GCL) and by their ability to generate large (> 500 pA) voltage-activated sodium currents. Spontaneous spiking was found in many RGNs prior to cell perfusion. Between postnatal day (P) 1 and 18, a total of 195 RGNs was tested for light-induced currents, conductance changes in response to exogenous glutamate (Glu) and γ-aminobutyric acid (GABA), and depolarizing or hyperpolarizing synaptic activity. The vast majority of the material was derived from RGNs at day P5. Whole-cell ion currents were always sampled at somatic sites, using either conventional or perforated patch whole-cell recordings. On day P5, 5% of tested RGNs ( n = 73) were already responsive to light stimulation. A higher percentage of cells (23%, n = 187) generated spontaneous depolarizing currents that were regarded as glutamatergic excitatory postsynaptic currents (EPSCs), since (1) they were blocked by Glu antagonists, (2) they conformed to the Na +/Cs + equilibrium potential, (3) and they displayed a time course characteristic of glutamatergic EPSCs. The mean EPSC amplitude was 19.0 pA (S.D. 11.83 pA). Amplitude distributions were fitted by multiple Gaussian equations rendering a quantal size of 6.6 to 9.1 pA at a holding voltage ( V h) of −70 mV (driving force about 70 mV). Spontaneous EPSCs were never observed under condition of Ca 2+-free solutions, but they persisted in the presence of tetrodotoxin. Bath application of quisqualate (500 μM) consistently increased EPSC frequencies. In contrast to the relatively high percentage of RGNs generating spontaneous EPSCs, very few RGNs at P5 (3%, n = 187) displayed inhibitory postsynaptic currents (IPSCs), although by that time all tested RGNs ( n = 14) were responsive to both exogenous Glu and GABA. These results indicate that in the postnatal rat retina development of excitatory synapses precedes the maturation of inhibitory afferents. Excitatory inputs to RGNs were to some extent functional before the animals opened their eyes. Glutamatergic synaptic activity may, thus, play an important role in shaping visual connections in the absence of visual experience.

Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain

An alteration in excitatory and inhibitory influences may underlie epilepsy. We used bilateral intrahippocampal microdialysis to test the hypothesis that an increase in extracellular glutamate may trigger spontaneous seizures. The concentrations of glutamate and γ-aminobutyric acid (GABA), the brain's major inhibitory neutrotransmitter, were measured in microdialysates before and during seizures in 6 patients with complex partial epilepsy investigated before surgery. Before seizures, concentrations of glutamate were higher in the epileptogenic hippocampus, whereas GABA concentrations were lower. During seizures, there was a sustained increase in extracellular glutamate to potentially neurotoxic concentrations in the epileptogenic hippocampus. Moreover, the increase preceded seizure. GABA concentrations were unchanged before seizures, but increased during them, with a greater rise in the non-epileptogenic hippocampus, suggesting that a rise in extracellular glutamate may precipitate seizures and that the concentrations reached may cause cell death.

Presynaptic inhibition by clonidine of neurotransmitter amino acid release in various brain regions

The release of endogenoue aspartic acid (Asp), glutamic acid (Glu) and γ-aminobutyric acid (GABA) was investigated in synaptosomes prepared from various regions of the brain. The basal release of Asp, Glu and GABA from various regions was 12–35, 24–107 and 15–43 pmol/min per mg protein, respectively. Exposure to a depolarizing concentration of KCl (30 mM) resulted in 1.7 to 3.6-fold increases in Asp. Glu and GABA release. When clonidine (10 −4 M) was added to the perfusion medium, the K +-evoked overflow of both Asp and Glu was inhibited by 50-–90% in the anterior cortex, thalamus and hypothalamus. Clonidine inhibited the K +-evoked Glu overflow by 30–40% in ht posterior cortex and hippocampus. No significant effects were observed in the other brain regions (olfactory bulb, striatum, midbrain, cerebellum, pons, medulla oblongata). The inhibitory effects of clonidine were counteracted by an ⨿ 2 adrenoceptor antagonists, rauwolscine. The data suggest that the basal and K +-evoked of Asp, Glu and GABA from nerve terminals is different in rat brain regions and that the presynaptic β 2-adrenoceptors which regulate the release of excitatory amino acids are mainly distributed in the anterior cerebral cortex, thalamus and hypothalamus of the rat brai.

Changes in the Sensory Processing of Olfactory Signals Induced by Birth in Sleep

After giving birth, sheep and many other species form a selective bond with their offspring based on the sense of smell. Processing of olfactory signals is altered to allow the animals to perform this selective recognition. Lamb odors have little effect on either neurotransmitter release or electrical activity of neurons in the olfactory bulb before birth. However, after birth there is an increase in the number of mitral cells, the principal cells of the olfactory bulb, that respond to lamb odors, which is associated with increased cholinergic and noradrenergic neurotransmitter release. Selective recognition of lambs is accompanied by increased activity of a subset of mitral cells and release of glutamate and γ-aminobutyric acid (GABA) from the dendrodendritic synapses between the mitral and granule cells. The relation between the release of each transmitter after birth also suggests an increased efficacy of glutamate-evoked GABA release.

Glutamate-immunoreactive synapses on retrogradely-labelled sympathetic preganglionic neurons in rat thoracic spinal cord

Retrograde tracing with cholera toxin B subunit (CTB) combined with post-embedding immunogold labelling was used to demonstrate the presence of glutamate-immunoreactive synapses on sympathetic preganglionic neurons that project to the adrenal medulla or to the superior cervical ganglion in rat thoracic spinal cord. At the electron microscope level, glutamate-immunoreactive synapses were found on retrogradely labelled nerve cell bodies and on dendrites of all sizes. Two-thirds of the vesicle-containing axon profiles that were directly apposed to, or synapsed on, CTB-immunoreactive sympathoadrenal neurons were glutamate positive. The proportion of glutamate-immunoreactive contacts and synapses on sympathoadrenal neurons decreased to zero when the anti-glutamate antiserum was absorbed with increasing concentrations of glutamate from 0.1 mM to 10mM. Double immunogold labelling for glutamate and γ-aminobutyric acid (GABA) showed that glutamate-immunoreactive profiles did not contain GABA and that GABA-immunoreactive profiles did not contain glutamate. These results suggest that glutamate is the major excitatory neurotransmitter to sympathoadrenal neurons and possibly to other sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord.

Intracerebroventricular administration of neuropeptide Y affects parameters of dopamine, glutamate and GABA activities in the rat striatum

The effects of intracerebroventricular (ICV) injection of neuropeptide Y (NPY) on parameters of dopamine (DA), glutamate (Glu) and γ-aminobutyric acid (GABA) activities were investigated in the rat striatum. NPY (1.17–4.70 nmol) induced a dose-dependent increase in the striatal endogenous DA release monitored in freely moving animals by means of a voltammetric method. Maximal increase was observed about one hour after the peptide injection. This result is consistent with the hypothesis that NPY may influence striatal DA turnover in a facilitatory manner by activating DA release. DA, DOPAC, Glu and GABA endogenous contents as well as 3H-Glu and 3H-GABA synaptosomal high affinity uptakes were examined one hour after NPY ICV administration at the same dose range in chloral hydrate-anesthetized animals. Depending on the NPY dose injected, opposite changes in Glu uptake were observed, suggesting that NPY has a bimodal influence on glutamatergic transmission. The Glu uptake rate increased markedly at 1.17 nmol NPY and decreased at 4.70 nmol, which may reflect an activation and an inhibition of the striatal Glu transmission, respectively. In parallel, the GABA uptake was found to decrease slightly at the higher doses of NPY tested, whereas no significant alteration of the striatal concentrations of either DA, DOPAC, Glu or GABA was observed. These results indicate that NPY may be involved in regulating the activity of nigral dopaminergic and cortical glutamatergic afferent pathways and that of intrinsic GABA neurons in the rat striatum.

Distinct, developmentally regulated brain mRNAs direct the synthesis of neurotransmitter transporters.

The Xenopus laevis oocyte expression system was utilized to define developmental and structural properties of neurotransmitter transporter mRNAs and the pharmacological characteristics of encoded carriers independent of the complexities of brain tissue preparations. Poly(A)+ RNA from dissected brain regions of neonatal and adult rats was microinjected into Xenopus oocytes and the expression of Na(+)-dependent neurotransmitter transporters determined 48 h later. Transport studies conducted with oocytes injected with RNAs derived from juvenile rat tissues indicate a region- and transporter-specific, postnatal increase in mRNA abundance as a major factor in the developmental changes observed for brain high-affinity amino acid uptake systems. Both L-glutamic acid (Glu) and gamma-aminobutyric acid (GABA) uptake systems were detectable by day 3 in postnatal forebrain mRNA and became progressively enriched during the next 2 weeks of forebrain development. In contrast, brainstem Glu and GABA transporter enrichment was 60-70% of adult values by day 3 and exceeded adult levels by day 10. Parallel determinations of L-glutamic acid decarboxylase mRNA abundance during development argue for distinct regulatory influences on mRNAs directing transmitter synthesis and reuptake. Glycine uptake could not be detected at any point of forebrain development and exhibited a gradual postnatal rise to adult levels over the first 3 postnatal weeks of brainstem development. Uptake studies conducted with well-characterized inhibitors of Glu, GABA, dopamine, and choline transport (D-aspartate, nipecotic acid, nomifensine, and hemicholinium-3, respectively) revealed that oocyte transporters encoded by adult rat brain mRNAs retained antagonist sensitivities exhibited by in vitro brain preparations. In addition, a differential regional sensitivity to the Glu transport antagonist dihydrokainate (1 mM) was observed, lending support to previous reports of region-specific Glu transporter subtypes. To determine the structural diversity present among brain transporter mRNAs, poly(A)+ RNA was size-fractionated on linear (10-31%) sucrose density gradients prior to oocyte injection. These experiments revealed two mRNA size classes (2.4-3.0 kb, 4.0-4.5 kb) independently capable of directing the synthesis of Glu, GABA, and glycine transporters. In regions other than the cerebellum, Glu and GABA transporter activities migrated as single, yet distinct, peaks of 4.0-4.5 kb. In contrast, both Glu and GABA transporters exhibited major peaks of activity at 2.5-3.0 kb with size-fractionated cerebellar mRNA. Brainstem glycine uptake exhibited a broad sedimentation profile, with peaks apparent at 2.4 and 4.0 kb. Taken together, these findings indicate previously unappreciated complexity in mRNA structure and regulation which underlies the expression of amino acid neurotransmitter uptake systems in the rodent CNS.

Action of Taurine, 3-aminopropanesulfonic acid, and GABA on the hindgut and heart of the cockroach,Leucophaea maderae

Taurine, glycine, glutamate, and gamma-aminobutyric acid (GABA) were all present in concentrations of greater than 1% of the total free amino acid content in the brain, thoracic, and abdominal ganglia of Leucophaea maderae. Hemolymph, subesophageal ganglia, and hindgut had substantial amounts of glutamate and glycine, but less than 0.3% taurine or GABA. Taurine, 3-aminopropanesulfonic acid (3-APS), cysteine-sulfinic acid (CSA), and GABA each had myotropic activity on the isolated cockroach hindgut, with 3-APS having the most consistent effect (ED50 = 0.63 mM), while taurine and CSA activities were similar to that of GABA on the hindgut. Both taurine and 3-APS had anti-arrhythmic effects on semi-isolated heart preparations of L. maderae, while GABA was inhibitory and induced arrhythmia. Bicuculline was antagonistic to the effects of GABA, taurine, and 3-APS on the hindgut, and induced arrhythmia in heart preparations; this arrhythmia was reversible by taurine, but not by GABA or 3-APS.

Evidence of glutamatergic deficiency in schizophrenia

Studies of amino acid release were carried out using frozen sections from brains of schizophrenics and controls. Synaptosomes were prepared via differential centrifugation in Ficoll allowing the veratridine-induced release of aspartate, glutamate, glycine, and GABA to be measured. The release of glutamate and γ-aminobutyric acid (GABA) was reduced in the synaptosomes from schizophrenics. This decrease could be reversed partially by pre-incubation of the synaptosomes with haloperidol. Additionally, the activity of glutamate decarboxylase was decreased and partially restored by haloperidol pre-incubation. These data are consistent with the hypothesis of a glutamatergic/GABAergic deficit in schizophrenia.

Effects of free fatty acids, ethanol and development on γ-aminobutyric acid and glutamate fluxes in rat nerve endings

The effects of type A ( cis-unsaturated) and type B ( trans-unsaturated and saturated) fatty acids, 1% and 3% ethanol (v/v), and development (7 days) on the thermodynamics of glutamate and γ-aminobutyric acid (GABA) transport into cortical rat brain nerve endings were examined. The effects of the various manipulations, which are known to affect membrane fluidity, may be summarized. Three percent ethanol and oleic acid increased ΔS° and ΔS † for glutamate transport and decreased ΔH° and ΔH † . Type B fatty acids had the opposite effects. In comparison to glutamate transport, GABA transport was less affected by the various manipulations and showed less specificity in terms of the fatty acid effects. Similarly, the effects of development on the thermodynamic parameters for glutamate and GABA transport were not consistent. Glutamate transport into 7-day nerve endings showed thermodynamic behavior similar to that seen when type A fatty acids were incorporated into adult nerve endings. In contrast, GABA transport into 7-day nerve endings had the character of adult nerve endings into which type B fatty acids were incorporated.

The effect of cochlear nerve lesion on the release of glutamate, aspartate, and GABA from cat cochlear nucleus, in vitro.

Pool studies of glutamate and aspartate have suggested a transmitter role for these amino acids in cochlear nerve endings. As further evidence. the K+-evoked release of glutamate, aspartate and GABA was measured in cat cochlear nucleus slices in vitro and compared to the release following a cochlear nerve lesion. Using [3H]glutamine as precursor, the K+-evoked release of glutamate and γ-aminobutyric acid (GABA) was respectively 4.1 and 7.2 times the spontaneous release. Using [14C]glutamate as a marker, the K+-evoked release of glutamate and GABA was respectively 7.1 and 2.8 times the basal release. All K+-evoked releases were Ca++-dependent. Nine days after unilateral lesion of the cochlear nerve in the cat, the glutamate release decreased by about 75% on the lesioned side compared to the intact one, whereas the GABA release was not decreased. The labelled tissue glutamate, either synthesized from [3H]glutamine or labelled with [14C]glutamate, was also markedly decreased on the lesioned side. In comparison, the evoked release of aspartate, newly synthesized from [14C]glutamate, remained low and was only decreased by about 45% after cochlear nerve lesions. Comparing cat with rat cochlear nucleus, the glutamate release was similar in both animals, whereas the GABA release was much higher in the rat. It is concluded that glutamate and to a lesser extent aspartate are likely to be released from cochlear nerve terminals, supporting a transmitter role in these nerve fibres for both amino acids.

Conversion of glucose to neurotransmitter amino acids in the brains of young and aging rats

Aspartate, glutamate and γ-aminobutyric acid (GABA) are thought to be neurotransmitters in certain areas of brain. These amino acids are rapidly synthesized from glucose in brain. The conversion of glucose carbon to these amino acids in cerebrum and in hindbrain of young (3-month-old) and old (22-month-old, “aged”) rats was studied. Radiolabeled glucose was injected into the rats, and the animals were killed 5 min later and their brains rapidly removed. The amounts of radioactivity present as glutamate and as aspartate, but not as GABA, were less in extracts of cerebrum in the aged rats than in the controls. In addition, the concentrations of glutamate were lower in cerebrum. Only minor changes either in the concentration or in the synthesis of these amino acids were apparent in hindbrains of the 22-month-old rats. Pyridoxal 5′-phosphate is a coenzyme in a number of the reactions whereby glutamate and aspartate are formed from intermediates of glucose metabolism, and the concentrations of pyridoxal 5′-phosphate were clearly reduced throughout the brains in the older rats. However, because the reduction in pyridoxal 5′-phosphate was greater in hindbrain than in cerebrum in the aged rats it seemed unlikely that this was the factor responsible for the reduction in the conversion of carbon from glucose to aspartate and glutamate, because this was much more pronounced in the cerebrum. Aspartate and glutamate are excitatory neurotransmitters, and if a similar slowing of their synthesis occurs in man to that observed in the present study in rats this might account for some of the distressing changes (loss of mental acuity, diminished reactivity, confusion) occasionally seen in elderly individuals.