Chronic stress induces neurochemical changes that include neurotransmitter imbalance in the brain. Noise is an environmental factor inducing stress. Chronic noise stress affects monoamine neurotransmitter systems in the central nervous system. The effect on other excitatory and inhibitory neurotransmitter systems is not known. The aim was to study the role of chronic noise stress on the glutamatergic and gamma-aminobutyric acid (GABA)ergic systems of the brain. Female Wistar rats (155 ± 5 g) were unintentionally exposed to noise due to construction (75-95 db, 3-4 hours/day, 5 days a week for 7-8 weeks) in the vicinity of the animal care facility. Glutamate/GABA levels and their metabolic enzymes were evaluated in different rat brain regions (cortex, hippocampus, striatum, and cerebellum) and compared with age and gender matched nonexposed rats. Chronic noise stress decreased glutamate levels and glutaminase activity 27% and 33% in the cortex, 15% and 24% in the cerebellum. Glutamate levels increased 10% in the hippocampus, 28% in striatum and glutaminase activity 15% in striatum. Glutamine synthetase activity increased significantly in all brain regions studied, that is, cortex, hippocampus, striatum, and cerebellum (P < 0.05). Noise stress-increased GABA levels and glutamate alpha decarboxylase activity 20% and 45% in the cortex, 13% and 28% in the hippocampus respectively. GABA levels and glutamate alpha decarboxylase activity decreased 15% and 14%, respectively in the striatum. GABA transaminase activity was significantly reduced in the cortex (55%), hippocampus (17%), and cerebellum (33%). Chronic noise stress differentially affected glutamatergic and GABAergic neurotransmitter systems in the rat brain, which may alter glutamate and GABA neurotransmission.
Keywords: Brain, glutamate, gamma-aminobutyric acid, noise stress
|How to cite this article:|
Kazi AI, Oommen A. Chronic noise stress-induced alterations of glutamate and gamma-aminobutyric acid and their metabolism in the rat brain. Noise Health 2014;16:343-9
| Introduction|| |
Environmental noise is a common problem encountered in urban life regarded to evoke stress and risk factor to human health. , Stress-induced responses are accomplished by stereotypic changes such as activation of the hypothalamic pituitary adrenal axis resulting in the release of corticosteroid hormone into the circulation and neurotransmitter activation in the brain. , Various stressors modulate neurochemical changes by altering neurotransmitter systems in the brain. , Acute stress-induced increase in neuro-endocrine and neurotransmitter levels in the brain may be adaptive responses to counteract the effect of stress,  while prolonged changes in neurotransmitter levels in response to chronic stress may disrupt homeostasis. , Thus, stress can lead to multiple effects depending on the nature of the stressor.  Noise stress has been shown to alter neurotransmitter levels in the brain  and reduce dendrite growth that are implicated in impaired memory and cognition in rats. ,
Acute and chronic noise stress result in the release of biogenic amines  and other neurotransmitters, acetylcholine, glutamate, and gamma-aminobutyric acid (GABA) in the brain. , Chronic noise stress-induced increase in the levels of brain dopamine and norepinephrine arise as a consequence of their increased synthesis and utilization.  The levels of other neurotransmitters may also be reflected in their use and metabolism. Chronic noise stress-induced modulation of glutamate and GABA, the principal excitatory and inhibitory neurotransmitters in the brain, is largely unknown.
Glutamate and GABA are ubiquitous in the brain and derived from a common precursor, glutamine. Astroglial derived glutamine serves as the main source for glutamate/GABA in glutamatergic and GABAergic neurons.  Neuronal hydrolysis of glutamine by glutaminase is the main source of the excitatory neurotransmitter glutamate,  while glial specific glutamine synthetase is involved in the regulation of glutamate by astrocyte uptake of glutamate and conversion to glutamine. GABA levels are regulated through synthesis from glutamate catalyzed by glutamate alpha decarboxylase (GAD) and metabolism to glutamate by GABA-transaminase (GABA-T), both synthesis and metabolism occurring in neurons.
Stress-induced changes affect both neuronal and glial metabolism that can affect glutamate and GABA levels. In the present study, the effect of chronic intermittent noise stress on the steady state levels of glutamate and GABA and their metabolic enzymes were studied in different regions of the rat brain. The levels of plasma corticosterone were recorded as an index of the stress response.
| Methods|| |
Bovine serum albumin (BSA), corticosterone, cumene hydroperoxide, GABA, glutamine, glutamic acid monosodium salt were from Sigma Chemical Company St. Louis, MO, USA. Adenosine-5΄-triphosphate (ATP), nicotinamide adenine dinucleotide (NAD + ), trichloroacetic acid (TCA) were from Sisco Research Laboratories, Mumbai, India. Hydrazine hydrate, hydroxyl amine hydrochloride, ferric chloride, and magnesium chloride were from Qualigens Fine Chemicals, Mumbai, India. L-glutamate dehydrogense was from Fluka Fine Chemicals, Buchs, Switzerland. All other chemicals were of analytical grade.
A total of 14 female Wistar rats weighing 155 ± 5 g, 6 months old were used. Animals were housed in polypropylene cages and were maintained at controlled ambient temperature (25 ± 2°C), relative humidity (50-70%) and exposed to 12 h dark - light cycle and allowed access to food (Rat Chow, VRK Nutritional Solutions, Sangli, Maharashtra, India) and water ad libtum. The experimental protocol and animal handling were in accordance with the guidelines of the Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA, Government of India).
Chronic noise stress exposure
Rats individually housed in polycarbonate cages were unintentionally exposed to noise due to construction taking place in the vicinity of the animal care facility where these rats were housed. Construction induced noise stress was retrospectively noticed. The generated noise was of an intensity of 75-95 db, equivalent to occupational exposure provoking stress. , The noise level was measured with a sound meter (Cirrus Research plc, UK, accuracy ±2 db). Noise exposure was 3-4 h/day between 10:00 am and 6:00 pm, 5 days a week for 7-8 weeks. Age, sex, and weight-matched rats housed separately in a noise free environment served as controls (155 ± 5 g, 6 months old, n = 7). The background noise level of control rats was below 40 db (Cirrus Research plc, UK).
Chronic noise stressed and nonstressed animals (seven animals per group) were sacrificed under ether anesthesia, blood drawn by cardiac puncture and serum separated by centrifugation. After being sacrificed, brains were quickly removed and dissected on ice as described by Spijker  to obtain cortex, striatum, hippocampus, and cerebellum. Tissues were snap frozen in liquid nitrogen and stored at -70°C. Steady state levels of glutamate and the activities of its metabolic enzymes (glutaminase, glutamine synthetase), steady state levels of GABA and activities of its metabolic enzymes GAD, GABA-T were determined in different regions of rat brain.
Determination of plasma corticosterone
Plasma corticosterone was assayed by the spectrofluorometric method of Glick et al. Fluorescence was read at λEx 462 nm/λEm 512 nm. Samples were read against a corticosterone standard between 100 and 500 ng and expressed as μg/dL.
A 10% (w/v) brain tissue homogenate was prepared in ice cold potassium phosphate buffer (50 mM, pH 7.0) at 4°C. An aliquot of the homogenate was immediately deproteinized with an equal volume of 10% TCA, centrifuged at 12,000 × g for 20 min at 4°C to obtain a protein-free supernatant, which was used for neurotransmitter (glutamate, GABA) analysis. Tissue homogenates were immediately assayed for glutamate alpha decarboxylase (GAD), GABA-transaminase (GABA-T), and glutaminase activity. An aliquot of the homogenate stored at -70°C was assayed for glutamine synthetase activity 24 h later.
Glutamate levels were determined in rat brain regions by the enzymatic method described by Bernt and Bergmeyer.  The method is based on the dehydrogenation of glutamate by glutamate dehydrogenase coupled to NAD + and the amount of NADH formed estimated spectrophotometrically at 340 nm. Glutamate levels were estimated from standards (10-50 nm) run in parallel and expressed as nmoles glutamate/mg protein.
Enzymes involved in glutamate metabolism
Glutaminase activity was measured as given by Graham and Aprison  and glutamate formed as a reaction product was estimated following the method of Bernt and Bergmeyer.  A 1 ml reaction mixture containing 0.1 M phosphate buffer (pH 8.1), glutamine (40 mM), and 10 μl of 10% brain homogenate was incubated at 37°C for 30 min, the reaction stopped with an equal volume of 10% TCA and glutamate estimated in 50 μl of protein free supernatant. Glutaminase activity was expressed as μmoles glutamate formed/h/mg protein.
Glutamine synthetase was assayed according to the method of Rowe et al.  A 1 ml of reaction of 0.1 M imidazole-HCl (pH 7.2), glutamate (50 mM), hydroxylamine-HCl (100 mM), MgCl 2 (20 mM), 2-mercaptoethanol (25 mM), and 100 μl of tissue homogenate, initiated with ATP (10 mM) was incubated at 37°C for 30 min. The reaction was stopped with 1.5 ml of 0.37 M FeCl 3 /0.67 M HCl/3 M TCA and gamma-glutamyl hydroxamate formed read at 540 nm. Enzyme activity was calculated from the molar extinction coefficient of gamma-glutamyl hydroxamate of 0.7 × 10 3 M/cm at 540 nm and expressed as μmoles of gamma-glutamyl hydroxamate formed/h/mg protein.
Gamma-aminobutyric acid estimation
Gamma-aminobutyric acid levels were determined in rat brain regions spectrofluorometrically by the method of Lowe et al.  as described by Uchida and O'Brein.  One volume of the tissue supernatant with two volumes of 14 mM ninhydrin (in 0.5 M carbonate-bicarbonate buffer pH 9.95) was heated at 60°C for 30 min, cooled to room temperature, followed by addition of 5 ml freshly prepared alkaline copper-tartrate reagent (10 mM sodium carbonate, 1.32 mM copper sulfate, and 2.2 mM tartaric acid), vortexed and incubated for 15 min at 25°C. GABA formed was estimated at λEx 377 nm/λEm 451 nm. Samples were read against a GABA standard and expressed as μg GABA/mg protein.
Enzymes involved in gamma-aminobutyric acid metabolism
Glutamate alpha decarboxylase
Glutamate alpha decarboxylase activity was assayed by the method of MacDonnell and Greengard,  followed by estimation of GABA formed. A reaction of 1 ml containing 0.1 M phosphate buffer (pH 6.4), 25 mM glutamate, 0.5 mM pyridoxal phosphate, 0.2% Triton X-100, and 100 μl of tissue homogenate (10% w/v) was incubated at 37°C for 30 min and the reaction terminated with 1 ml TCA (10%). The amount of GABA formed was determined by the method of Uchida and O'Brien.  GAD activity was expressed as μmoles GABA formed/h/mg protein.
Gamma-aminobutyric acid-transaminase activity was estimated by the method of Sytinsky et al.  A reaction of 1 ml containing 0.15 M Tris-HCl buffer (pH 8.6), 10 mM α-keto-glutarate, 20 mM 2-mercapto ethanol, 0.2% Triton X-100, and 100 μl of brain homogenate (10%), initiated with 10 mM GABA, was incubated 37°C for 30 min. The reaction was stopped with 1 ml TCA (10%) and the glutamate formed was estimated by the method of Bernt and Bergmeyer  in 50 μl protein free supernatant as given above. GABA-T activity was expressed as μmoles glutamate formed/h/mg protein.
Protein was estimated by the method of Lowry et al.  using BSA fraction V as standard.
All experiments were carried out independently in a minimum of seven animals in control and noise stress groups and duplicates for statistical validity. Data, expressed as mean ± standard deviation (SD) (n = 7) were analyzed for differences between noise stressed and nonstressed controls animals using the Student's t-test using SPSS version 16 statistical software (SPSS Inc, Chicago, Illinois, USA). Differences were considered as significant at a level of p < 0.05.
| Results|| |
Plasma corticosterone were 40 ± 3.89 μg/dL in noise stressed rats and significantly higher than levels in control rats of 23.3 ± 4.966 μg/dL (mean ± SD, n = 7, p < 0.05).
Effect of chronic noise stress on glutamate/gamma-aminobutyric acid levels in the rat brain
Noise stress significantly increased glutamate by 10% in hippocampus from a baseline value of 110 ± 2.7 nmol to 122 ± 3.2 nmol/mg protein and 28% in striatum from 85.9 ± 6.4 to 110 ± 4.2 nmol/mg protein compared to these regions of nonstressed rats (p < 0.05) [Figure 1]. Chronic noise stress significantly decreased glutamate by 27% in cortex from 105 ± 5.7 to 79 ± 1.6 nmol/mg protein and 15% in cerebellum from 101 ± 5.7 to 85 ± 4.1 nmol/mg protein compared to these regions of unstressed rats (P < 0.05).
|Figure 1: Effect of chronic noise stress on glutamate levels in rat brain regions. Data represents mean ± standard deviation for seven animals in each group in each region. *P < 0.05 compared to unstressed controls|
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Noise stress significantly increased GABA by 20% in cortex from 4.19 ± 0.14 to 5.24 ± 0.34 μg/mg protein and 15% in hippocampus from 4.10 ± 0.23 to 4.68 ± 0.14 μg/mg protein compared with nonstressed controls [Figure 2]. Noise stress significantly reduced GABA in striatum from 5.3 ± 0.2 to 4.8 ± 0.05 μg/mg protein and in cerebellum from 3.52 ± 0.14 to 3.1 ± 0.3 μg/mg protein compared with nonstressed controls (P < 0.05).
|Figure 2: Effect of chronic noise stress on gamma-aminobutyric acid levels in rat brain regions. Data represents mean ± standard deviation for seven animals in each group in each region. *P < 0.05 compared to unstressed controls|
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Effect of chronic noise stress on enzymes involved in glutamate metabolism in the rat brain
Chronic noise stress significantly increased glutamine synthetase in all brain regions studied compared to nonstressed rats (P < 0.05), 30% in cortex, 27% in striatum, 75% in hippocampus, and 40% in cerebellum [Figure 3].
|Figure 3: Effect of chronic noise stress on glutaminase activity in rat brain regions. Data represents mean ± standard deviation for seven animals in each group in each region. *P < 0.05 compared to unstressed controls|
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Chronic noise stress significantly decreased glutaminase by 33% in the cortex and 24% in cerebellum and significantly increased activity by 15% in striatum compared to nonstressed rats (P < 0.05) [Figure 4]. Noise stress did not alter glutaminase activity in the hippocampus.
|Figure 4: Effect of chronic noise stress on glutamine synthetase activity in rat brain regions. Data represents mean ± standard deviation for seven animals in each group in each region. *P < 0.05 compared to unstressed controls|
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Effect of chronic noise stress on enzymes involved in gamma-aminobutyric acid metabolism in the rat brain
Glutamate alpha decarboxylase activity
Chronic noise stress significantly increased GAD activity 45% in the cortex and 28% in the hippocampus and decreased GAD activity by 14% in striatum compared to nonstressed rats (P < 0.05) [Figure 5]. Noise stress did not alter GAD activity in the cerebellum compared to nonstressed rats.
|Figure 5: Effect of chronic noise stress on glutamate alpha decarboxylase activity in rat brain regions. Data represents mean ± standard deviation for seven animals in each group in each region. *P < 0.05 compared to unstressed controls|
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Gamma-aminobutyric acid-transaminase activity
Chronic noise stress significantly decreased GABA-T activity by 55% in cortex, 17% in hippocampus and 30% in cerebellum (P < 0.01) [Figure 6]. Noise stress did not alter GABA-T activity in hippocampus and striatum compared to nonstressed controls.
|Figure 6: Effect of chronic noise stress on gamma-aminobutyric acid-transaminase activity in rat brain regions. Data represents mean ± standard deviation for seven animals in each group in each region. *P < 0.05 compared to unstressed controls|
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| Discussion|| |
Noise is known to induce stress and our finding that chronic noise exposure increased basal corticosterone levels were evidence of stress induction in rats. This has been previously demonstrated by Manikandan et al.  In this study, it was found that chronic noise exposure differentially affected the steady state levels of glutamate and GABA in different regions of the rat brain. The present study also contributes to understanding the metabolic regulation of excitatory and inhibitory neurotransmitters, glutamate and GABA respectively, in the brain by chronic noise.
Effect of chronic noise stress on the glutamate system
The hippocampus is an important target for detrimental effects of stress  and stress-induced alterations in hippocampal neurons are reported to underlie cognitive and memory deficits. ,, Noise stress-induced neuronal release of glutamate is well-documented , and as observed in the present study, chronic noise stress has been shown to increase glutamate in the hippocampus. , The hippocampus also displays a high density of glucocorticoid receptors , and stress induced glucocorticoid release of glutamate has been shown to promote neuronal damage. 
In the present study, decrease in glutaminase activity (i.e., synthesis of glutamate) in cortex and cerebellum accounts for the reduced glutamate levels [Figure 4] and increased activity for increased glutamate in the striatum. Noise stress increased glutamine turnover from glutamate by enhanced glutamine synthetase activity in all brain regions [Figure 3]. This glial specific enzyme is inducible, responsive to glutamate and regulates glutamate levels released at the synaptic cleft. , Stress induced increase in glutamine synthetase has been reported earlier by Radαk et al. following hypoxic stress.  Enhanced glutamine synthetase activity may be indicative of increased glutamate toxicity in the brain. Although increase in glutamine synthetase activity is observed in striatum, the high glutamate levels indicate greater synthesis and/or decreased clearance of glutamate. In restrain stress, high-affinity glutamate uptake is enhanced in most forebrain regions, but not in the striatum. 
Effect of stress on gamma-aminobutyric acid metabolism
Stress also has an effect on GABA, which is also stressor dependent. Decrease in GABA content following chronic cold stress is observed in the cortex, hypothalamus and olfactory bulb  while chronic immobilization stress increased cortical GABA.  Chronic noise stress has been reported to decrease hippocampal GABA. 
In the present study, GABA levels were significantly decreased in striatum while the levels were high in hippocampus of noise stressed rats [Figure 2]. Although reduced glutamate levels can affect GABA synthesis as glutamate is the immediate precursor of GABA  in the present study decrease in striatal GABA was associated with reduced GAD activity, while enhanced GAD activity in the cortex and hippocampus may account for the increase in GABA levels. Region specific enhancement of GAD activity and mRNA levels have been reported following chronic heat stress  and restraint stress.  Reduction in GABA-T activity can act to maintain GABA levels. Enhanced GABA levels in the cortex and normal levels in the cerebellum where glutamate levels are reduced may also result from decreased GABA-T activity in these regions [Figure 6]. Our findings differ from those of Cui et al.  in that increased GABA is observed in the hippocampus supported through increased GAD activity.
Increased GABA levels ameliorate glutamate toxicity.  Inhibitors of GABA-T that enhance GABA reduce glutamate excitation. , This has been well-demonstrated in mice susceptible to audiogenic seizures.  The present data show that chronic noise stress induced changes in GABA in rat brain regions are regulated by alterations in the activities of enzymes involved in GABA synthesis and degradation.
| Conclusion|| |
Chronic noise stress affects glutamatergic and GABAergic systems differently in different rat brain regions. Glutamatergic systems were enhanced in hippocampus and striatum while enhanced GABA levels were observed in cortex and hippocampus. Further studies are required to evaluate the neurotransmitter receptor associated changes and pathology induced by noise stress.
| Acknowledgment|| |
A.I.K. acknowledges the Indian Council for Medical Research (New Delhi) for a Senior Research Fellowship (No-3/1/2/1(ENV)/ 2009-NCD-1).
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Dr. Amajad Iqbal Kazi
CITB Plot No. 54, Michigan Compound, Saptapur, Dharwad - 580 001, Karnataka
Source of Support: Indian Council for Medical Research (New Delhi)., Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]