Concentrations Of Excitatory Neurotransmitters Research Articles

The effect of valproate on the amino acids, monoamines, and kynurenic acid concentrations in brain structures involved in epileptogenesis in the pentylenetetrazol-kindled rats.

The study aimed to assess the influence of a single valproate (VPA) administration on inhibitory and excitatory neurotransmitter concentrations in the brain structures involved in epileptogenesis in pentylenetetrazol (PTZ)-kindled rats. Adult, male Wistar rats were kindled by repeated intraperitoneal (ip) injections of PTZ at a subconvulsive dose (30mg/kg, three times a week). Due to the different times required to kindle the rats (18-22 injections of PTZ), a booster dose of PTZ was administrated 7days after the last rats were kindled. Then rats were divided into two groups: acute administration of VPA (400mg/kg) or saline given ip. The concentration of amino acids, kynurenic acid (KYNA), monoamines, and their metabolites in the prefrontal cortex, hippocampus, amygdala, and striatum was assessed by high-pressure liquid chromatography (HPLC). It was found that a single administration of VPA increased the gamma-aminobutyric acid (GABA), tryptophan (TRP), 5-hydroxyindoleacetic acid (5-HIAA), and KYNA concentrations and decreased aspartate (ASP) levels in PTZ-kindled rats in the prefrontal cortex, hippocampus, amygdala and striatum. Our results indicate that a single administration of VPA in the PTZ-kindled rats restored proper balance between excitatory (decreasing the level of ASP) and inhibitory neurotransmission (increased concentration GABA, KYNA) and affecting serotoninergic neurotransmission in the prefrontal cortex, hippocampus, amygdala, and striatum.

Impact of Transcranial Direct Current Stimulation and Cognitive Training on Frontal Lobe Neurotransmitter Concentrations.

Objective: This study examines the impact of transcranial direct current stimulation (tDCS) combined with cognitive training on neurotransmitter concentrations in the prefrontal cortex.Materials and Methods: Twenty-three older adults were randomized to either active-tDCS or sham-tDCS in combination with cognitive training for 2 weeks. Active-tDCS was delivered over F3 (cathode) and F4 (anode) electrode placements for 20 min at 2 mA intensity. For each training session, 40-min of computerized cognitive training were applied with active or sham stimulation delivered during the first 20-min. Glutamine/glutamate (Glx) and gamma-aminobutyric acid (GABA) concentrations via proton magnetic resonance spectroscopy were evaluated at baseline and at the end of 2-week intervention.Results: Glx concentrations increased from pre- to post-intervention (p = 0.010) in the active versus sham group after controlling for age, number of intervention days, MoCA scores, and baseline Glx concentration. No difference in GABA concentration was detected between active and sham groups (p = 0.650) after 2-week intervention.Conclusion: Results provide preliminary evidence suggesting that combining cognitive training and tDCS over the prefrontal cortex elicits sustained increase in excitatory neurotransmitter concentrations. Findings support the combination of tDCS and cognitive training as a potential method for altering neurotransmitter concentrations in the frontal cortices, which may have implications for neuroplasticity in the aging brain.

Visual Attention Modulates Glutamate-Glutamine Levels in Vestibular Cortex: Evidence from Magnetic Resonance Spectroscopy.

Attending to a stimulus enhances the neuronal responses to it, while responses to nonattended stimuli are not enhanced and may even be suppressed. Although the neural mechanisms of response enhancement for attended stimuli have been intensely studied, the neural mechanisms underlying attentional suppression remain largely unknown. It is uncertain whether attention acts to suppress the processing in sensory cortical areas that would otherwise process the nonattended stimulus or the subcortical input to these cortical areas. Moreover, the neurochemical mechanisms inducing a reduction or suppression of neuronal responses to nonattended stimuli are as yet unknown. Here, we investigated how attention directed toward visual processing cross-modally acts to suppress vestibular responses in the human brain. By using functional magnetic resonance spectroscopy in a group of female and male subjects, we find that attention to visual motion downregulates in a load-dependent manner the concentration of excitatory neurotransmitter (glutamate and its precursor glutamine, referred to together as Glx) within the parietoinsular vestibular cortex (PIVC), a core cortical area of the vestibular system, while leaving the concentration of inhibitory neurotransmitter (GABA) in PIVC unchanged. This makes PIVC less responsive to excitatory thalamic vestibular input, as corroborated by functional magnetic resonance imaging. Together, our results suggest that attention acts to suppress the processing of nonattended sensory cues cortically by neurochemically rendering the core cortical area of the nonattended sensory modality less responsive to excitatory thalamic input.SIGNIFICANCE STATEMENT Here, we address a fundamental problem that has eluded attention research for decades, namely, how the brain ignores irrelevant stimuli. To date, three classes of solutions to this problem have been proposed: (1) enhancement of GABAergic interneuron activity in cortex, (2) downregulation of glutamatergic cell activity in cortex; and (3) downregulation of neural activity in thalamic projection areas, which would then provide the cortex with less input. Here, we use magnetic resonance spectroscopy in humans and find support for the second hypothesis, implying that attention to one sensory modality involves the suppression of irrelevant stimuli of another sensory modality by downregulating glutamate in the cortex.

Transcranial photoacoustic imaging of NMDA-evoked focal circuit dynamics in the rat hippocampus

Objective. We report the transcranial functional photoacoustic (fPA) neuroimaging of N-methyl-D-aspartate (NMDA) evoked neural activity in the rat hippocampus. Concurrent quantitative electroencephalography (qEEG) and microdialysis were used to record real-time circuit dynamics and excitatory neurotransmitter concentrations, respectively. Approach. We hypothesized that location-specific fPA voltage-sensitive dye (VSD) contrast would identify neural activity changes in the hippocampus which correlate with NMDA-evoked excitatory neurotransmission. Main results. Transcranial fPA VSD imaging at the contralateral side of the microdialysis probe provided NMDA-evoked VSD responses with positive correlation to extracellular glutamate concentration changes. qEEG validated a wide range of glutamatergic excitation, which culminated in focal seizure activity after a high NMDA dose. We conclude that transcranial fPA VSD imaging can distinguish focal glutamate loads in the rat hippocampus, based on the VSD redistribution mechanism which is sensitive to the electrophysiologic membrane potential. Significance. Our results suggest the future utility of this emerging technology in both laboratory and clinical sciences as an innovative functional neuroimaging modality.

Change in Amino Acid Pools During Neuronal Differentiation of PC12 Cells.

Although rat PC12 cells are a well-established model to investigate neuronal differentiation, survival and function, the reports of differentiation-associated changes in the intracellular amino acid pools of neurotransmitters have been limited. In this study, possible changes in the intracellular amino acid pools were investigated during nerve growth factor (NGF)-induced differentiation of PC12 cells. Rat PC12 cells were induced to differentiate into neuronal cells by 50 ng/ml NGF in serum-free Dulbecco's Modified Eagle's medium, followed by the addition of fresh NGF-containing medium at day 3, without medium change. Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Intracellular amino acids were extracted by 5%trichloroacetic acid and quantified by amino acid analyzer. Differentiated PC12 cells showed high concentrations of excitatory neurotransmitters (glutamic acid and aspartic acid) and glutamine (energy supply). In contrast, urea and taurine levels declined with the progression of neuronal differentiation. Exogenous addition of taurine, urea, and L- and D- aspartic acid showed little or no effect on supporting viability of PC12 cells cultured in serum-free medium. The present study demonstrated dramatic changes in the composition of intracellular amino acids during neuronal differentiation.

Functional Connectivity Is Associated With Altered Brain Chemistry in Women With Endometriosis-Associated Chronic Pelvic Pain

In contrast to women with relatively asymptomatic endometriosis, women with endometriosis-associated chronic pelvic pain (CPP) exhibit nonpelvic hyperalgesia and decreased gray matter volume in key neural pain processing regions. Although these findings suggest central pain amplification in endometriosis-associated CPP, the underlying changes in brain chemistry and function associated with central pain amplification remain unknown. We performed proton spectroscopy and seed-based resting functional connectivity magnetic resonance imaging to determine whether women with endometriosis display differences in insula excitatory neurotransmitter concentrations or intrinsic brain connectivity to other pain-related brain regions. Relative to age-matched pain-free controls, women with endometriosis-associated CPP displayed increased levels of combined glutamine-glutamate (Glx) within the anterior insula and greater anterior insula connectivity to the medial prefrontal cortex (mPFC). Increased connectivity between these regions was positively correlated with anterior insula Glx concentrations (r = .87), as well as clinical anxiety (r = .61, P = .02), depression (r = .60, P = .03), and pain intensity (r = .55, P = .05). There were no significant differences in insula metabolite levels or resting-state connectivity in endometriosis patients without CPP versus controls. We conclude that enhanced anterior insula glutamatergic neurotransmission and connectivity with the mPFC, key regions of the salience and default mode networks, may play a role in the pathophysiology of CPP independent of the presence of endometriosis. PerspectiveSimilar to other chronic pain conditions, endometriosis-associated pelvic pain is associated with altered brain chemistry and function in pain processing regions. These findings support central pain amplification as a mechanism of chronic pelvic pain, and clinicians should consider the use of adjunctive therapies that target central pain dysfunction in these women.

Glutamatergic correlates of gamma-band oscillatory activity during cognition: A concurrent ER-MRS and EEG study

Frequency specific synchronisation of neuronal firing within the gamma-band (30–70Hz) appears to be a fundamental correlate of both basic sensory and higher cognitive processing. In-vitro studies suggest that the neurochemical basis of gamma-band oscillatory activity is based on interactions between excitatory (i.e. glutamate) and inhibitory (i.e. GABA) neurotransmitter concentrations. However, the nature of the relationship between excitatory neurotransmitter concentration and changes in gamma band activity in humans remains undetermined. Here, we examine the links between dynamic glutamate concentration and the formation of functional gamma-band oscillatory networks. Using concurrently acquired event-related magnetic resonance spectroscopy and electroencephalography, during a repetition-priming paradigm, we demonstrate an interaction between stimulus type (object vs. abstract pictures) and repetition in evoked gamma-band oscillatory activity, and find that glutamate levels within the lateral occipital cortex, differ in response to these distinct stimulus categories. Importantly, we show that dynamic glutamate levels are related to the amplitude of stimulus evoked gamma-band (but not to beta, alpha or theta or ERP) activity. These results highlight the specific connection between excitatory neurotransmitter concentration and amplitude of oscillatory response, providing a novel insight into the relationship between the neurochemical and neurophysiological processes underlying cognition.

Hypothermia after aneurysmal subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage (SAH) is a common and frequently devastating condition, accounting for 1 to 7% of all strokes with an incidence of 9.1 per 100,000 [1]. Major advances in SAH management over the past three decades have decreased case fatality by 0.8% per year, but it is still 40% and many survivors have long-term disabilities [2]. The most important and potentially treatable complication is development of delayed cerebral ischemia (DCI), which can progress to cerebral infarction associated with poor outcome. The pathogenesis of DCI is multifactorial and assumed to be initiated in the early phase of SAH [3]. The onset of SAH is characterized by a short-lasting and cerebral perfusion pressure (CPP)-dependent decrease in cerebral blood flow (CBF) leading to global cerebral ischemia [4]. Elevated intracranial pressure (ICP) and acute cerebral ischemia are the main factors for early disruption of the blood-brain barrier as well as impairment of autoregulation associated with brain edema and brain swelling. Important pathogenic mechanisms of CPP-independent hypoperfusion include acute vasoconstriction, cortical spreading ischemia, and activation of the inflammatory response. The release of oxyhemoglobin and endothelin-1 (ET-1) are the key factors for cortical spreading ischemia, reduced nitric oxide (NO) availability, and secondary cytotoxic edema formation. Cerebral vasospasm (CVS) is a delayed morphological narrowing of cerebral arteries, occurring 4 to 10 days after SAH. Although CVS have been associated with DCI, it is generally accepted that CVS is not solely responsible for DCI [5]. In fact, DCI may occur in the absence of CVS and vice versa and the distribution of CVS may fail to reliably predict the subsequent pattern of cerebral infarction [6]. Neuroprotective strategies to prevent DCI have been mainly focused on treatment of CVS, but despite extensive research, effective and/or causative prophylaxis and treatment are not available [7]. So far, oral nimodipine is the only drug that can reduce the incidence of DCI and poor outcome, but there is no beneficial effect on CVS [8]. Hypothermia (HT) treatment exerting numerous protective effects such as a decrease in cerebral metabolism [9], stabilization of the blood-brain barrier [10], reduction of cerebral edema [11], suppression of excitatory neurotransmitter concentrations [12] and inflammatory reactions [13] seems to be well suited as a neuroprotective strategy. In the following, the clinical application of HT after SAH is presented by reviewing the existing literature.

Proteolytic Activation of Monocyte Chemoattractant Protein-1 by Plasmin Underlies Excitotoxic Neurodegeneration in Mice

Exposure of neurons to high concentrations of excitatory neurotransmitters causes them to undergo excitotoxic death via multiple synergistic injury mechanisms. One of these mechanisms involves actions undertaken locally by microglia, the CNS-resident macrophages. Mice deficient in the serine protease plasmin exhibit decreased microglial migration to the site of excitatory neurotransmitter release and are resistant to excitotoxic neurodegeneration. Microglial chemotaxis can be signaled by the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 (CC chemokine ligand 2). We show here that mice genetically deficient for MCP-1 phenocopy plasminogen deficiency by displaying decreased microglial recruitment and resisting excitotoxic neurodegeneration. Connecting these pathways, we demonstrate that MCP-1 undergoes a proteolytic processing step mediated by plasmin. The processing, which consists of removal of the C terminus of MCP-1, enhances the potency of MCP-1 in in vitro migration assays. Finally, we show that infusion of the cleaved form of MCP-1 into the CNS restores microglial recruitment and excitotoxicity in plasminogen-deficient mice. These findings identify MCP-1 as a key downstream effector in the excitotoxic pathway triggered by plasmin and identify plasmin as an extracellular chemokine activator. Finally, our results provide a mechanism that explains the resistance of plasminogen-deficient mice to excitotoxicity.

Serial neurochemical measurement of cerebrospinal fluid during the human sexual response cycle

Recent studies examining the neuroendocrine response pattern underlying the human sexual response cycle revealed transient activation of the sympathoadrenal system and a substantial, long-lasting increase in plasma prolactin concentrations following orgasm in men and women. Prolactin has been discussed as being part of a feedback mechanism that signals centers in the central nervous system, such as the dopaminergic system controlling sexual arousal. To further elucidate the central role of neuropeptides, biogenic monoamines and neurotransmitters in human sexual behavior, a serial cerebrospinal fluid (CSF)-sampling technique was implemented using a previously established experimental paradigm for sexual activity in a laboratory setting. In parallel with peripheral endocrine measures, lumbar CSF was drawn via an indwelling spinal catheter during the sexual response cycle in 10 healthy males and 10 age-matched controls, and analysed for prolactin, oxytocin, biogenic monoamines and/or their metabolites as well as inhibitory and excitatory neurotransmitter concentrations. Parallel to raised peripheral sympathetic activity, norepinephrine also increased in CSF during audiovisual, masturbation-induced sexual arousal and orgasm, and remained elevated for the remainder of the session (F(4,72) = 8.79, P = 0.000). In contrast, none of the other measures, in particular prolactin and dopamine or its metabolites, reflected significant alteration. In conclusion, the human sexual response cycle is characterized by an increase in sympathetic activity in plasma and CSF, and by pronounced secretion of plasma prolactin after orgasm. However, alterations in dopaminergic or peptidergic activity are not found in lumbar CSF, possibly due to local and restricted release in diencephalic and mesencephalic brain regions.

The Presence of Female Hormone Receptors in the Nasal Mucosa

In contrast to women with relatively asymptomatic endometriosis, women with endometriosis-associated chronic pelvic pain (CPP) exhibit nonpelvic hyperalgesia and decreased gray matter volume in key neural pain processing regions. Although these findings suggest central pain amplification in endometriosis-associated CPP, the underlying changes in brain chemistry and function associated with central pain amplification remain unknown. We performed proton spectroscopy and seed-based resting functional connectivity magnetic resonance imaging to determine whether women with endometriosis display differences in insula excitatory neurotransmitter concentrations or intrinsic brain connectivity to other pain-related brain regions. Relative to age-matched pain-free controls, women with endometriosis-associated CPP displayed increased levels of combined glutamine-glutamate (Glx) within the anterior insula and greater anterior insula connectivity to the medial prefrontal cortex (mPFC). Increased connectivity between these regions was positively correlated with anterior insula Glx concentrations (r = .87), as well as clinical anxiety (r = .61, P = .02), depression (r = .60, P = .03), and pain intensity (r = .55, P = .05). There were no significant differences in insula metabolite levels or resting-state connectivity in endometriosis patients without CPP versus controls. We conclude that enhanced anterior insula glutamatergic neurotransmission and connectivity with the mPFC, key regions of the salience and default mode networks, may play a role in the pathophysiology of CPP independent of the presence of endometriosis.Similar to other chronic pain conditions, endometriosis-associated pelvic pain is associated with altered brain chemistry and function in pain processing regions. These findings support central pain amplification as a mechanism of chronic pelvic pain, and clinicians should consider the use of adjunctive therapies that target central pain dysfunction in these women.

Protective effect of galanin on behavioral deficits in experimental traumatic brain injury.

The magnitude of behavioral deficits in traumatic brain injury (TBI) has been shown to be partly related to alterations in the balance between excitatory and inhibitory neurotransmitter release. Previous studies have demonstrated that extracellular excitatory neurotransmitter concentrations dramatically increase following experimental TBI. We examined the effects of a neuromodulatory peptide, galanin (GAL), on behavioral morbidity, as measured by sensory motor and memory performance tasks, associated with experimental TBI in the rat. A single intraventricular injection of GAL (1.0 micrograms, n = 8 or 10.0 micrograms, n = 10) or cerebrospinal fluid (CSF) vehicle (n = 10) was administered 5 minutes prior to central fluid percussion TBI in rats. Performance on sensory motor tasks was assessed prior to injury and for 5 days after TBI with beam-balance, beam-walking, and rotarod tasks. Memory performance was assessed on days 11-15 after TBI with the Morris water maze. TBI produced significant motor and memory deficits in the CSF-treated group. GAL-treated rats had significantly less magnitude of deficits compared to CSF-treated rats on beam-balance, beam-walking, and rotarod performance. The 1.0 micrograms GAL dose produced slightly greater protection than the 10.0 micrograms GAL dose. Neither GAL dose affected body weight loss or Morris water maze performance. These results suggest that the physiologic effects of GAL may reduce certain components of TBI morbidity, possibly by modulating neuronal excitability.

Glucocorticoid endangerment of hippocampal neurons is NMDA-receptor dependent

The adrenal stress hormones glucocorticoids (GCs) impair the ability of hippocampal neurons to survice neurological insults, including hypoxia-ischemia and seizure. These insults are thought to be toxic via a cascade of excessive synaptic concentrations of excitatory neurotransmitters (e.g. glutamate), activation of the NMDA receptor, and pathologic mobilization of cytosolic calcium post-synaptically. We tested whether GCs exacerbate these insults by exacerbating this ‘NMDA cascade’. We sought a toxin which damaged independently of the NMDA cascade, and whose toxicity was enhanced by GCs. After testing a number of neurotoxins, we found that the antimetabolite 3-acetylpyridine (3AP) fit this requirement. We then tested if blockade of the NMDA receptor blocks the ability of GCs to enhance 3AP toxicity. Hippocampi were microinfused with 160 μg of 3AP. Elevating circulating GC concentrations to the range seen during major stresses for a week before and after microinfusion caused a significant in 3AP-induced damage (when compared to adrenalectomized rats kept GC-free for the same period). Infusing the NMDA receptor blocker APV with 3AP did not alter the toxicity in adrenalectomized rats. However, APV reduced 3AP-induced damage in GC-treated rats to levels seen in adrenalectomized rats. This suggests that GCs endanger hippocampal neurons by enhancing glutamatergic signals and/or enhancing vulnerability to such signals. As a possible explanation for this observation, GCs inhibit glucose uptake into hippocampal neurons, and numerous steps in the NMDA cascade are exacerbated when neuronal energy stores are diminished.