Brain GABA Research Articles

Brain GABA and Glutamate Concentrations Following Chronic Gabapentin Administration: A Convenience Sample Studied During Early Abstinence From Alcohol.

Gabapentin (GBP), a GABA analog that may also affect glutamate (Glu) production, can normalize GABA and Glu tone during early abstinence from alcohol, effectively treating withdrawal symptoms and facilitating recovery. Using in vivo magnetic resonance spectroscopy, we tested the degree to which daily GBP alters regional brain GABA and Glu levels in short-term abstinent alcohol-dependent individuals. Regional metabolite levels were compared between 13 recently abstinent alcohol-dependent individuals who had received daily GBP for at least 1 week (GBP+) and 25 matched alcohol-dependent individuals who had not received GBP (GBP−). Magnetic resonance spectra from up to five different brain regions were analyzed to yield absolute GABA and Glu concentrations. GABA and Glu concentrations in the parieto-occipital cortex were not different between GBP− and GBP+. Glu levels in anterior cingulate cortex, dorsolateral prefrontal cortex, and basal ganglia did not differ between GBP− and GBP+. However, in a subgroup of individuals matched on age, sex, and abstinence duration, GBP+ had markedly lower Glu in the frontal white matter (WM) than GBP−, comparable to concentrations found in light/non-drinking controls. Furthermore, lower frontal WM Glu in GBP+ correlated with a higher daily GBP dose. Daily GBP treatment at an average of 1,600 mg/day for at least 1 week was not associated with altered cortical GABA and Glu concentrations during short-term abstinence from alcohol, but with lower Glu in frontal WM. GBP for the treatment of alcohol dependence may work through reducing Glu in WM rather than increasing cortical GABA.

RP-HPLC method for simultaneous estimation of vigabatrin, gamma-aminobutyric acid and taurine in biological samples

Vigabatrin is used as first line drug in treatment of infantile spasms for its potential benefit overweighing risk of causing permanent peripheral visual field defects and retinal damage. Chronic administration of vigabatrin in rats has demonstrated these ocular events are result of GABA accumulation and depletion of taurine levels in retinal tissues. In vigabatrin clinical studies taurine plasma level is considered as biomarker for studying structure and function of retina. The analytical method is essential to monitor taurine levels along with vigabatrin and GABA. A RP-HPLC method has been developed and validated for simultaneous estimation of vigabatrin, GABA and taurine using surrogate matrix. Analytes were extracted from human plasma, rat plasma, retina and brain by simple protein precipitation method and derivatized by naphthalene 2, 3‑dicarboxaldehyde to produce stable fluorescent active isoindole derivatives. The chromatographic analysis was performed on Zorbax Eclipse AAA column using gradient elution profile and eluent was monitored using fluorescence detector. A linear plot of calibration curve was observed in concentration range of 64.6 to 6458, 51.5 to 5150 and 62.5 to 6258 ng/mL for vigabatrin, GABA and taurine, respectively with r2 ≥ 0.997 for all analytes. The method was successfully applied for estimating levels of vigabatrin and its modulator effect on GABA and taurine levels in rat plasma, brain and retinal tissue. This RP-HPLC method can be applied in clinical and preclinical studies to explore the effect of taurine deficiency and to investigate novel approaches for alleviating vigabatrin induced ocular toxicity.

Pyridazinone hybrids: Design, synthesis and evaluation as potential anticonvulsant agents

A series of new hybrid benzothiazole containing pyridazinones derivatives were designed and synthesized fulfilling all the pharmacophoric requirements essential for the anticonvulsant activity. In-silico and in vitro studies revealed that some of these hybrid derivatives demonstrated admirable GABA AT inhibitory activity. An attempt has also been made to validate the results of in vitro GABA AT inhibition of the most potent compound SPS-5F (IC50 9.10 μM) through in vivo anticonvulsant screening. Compound SPS-5F administration significantly increases the whole brain GABA level, might be through the inhibition of GABA AT enzyme.

Endosulfan and its toxicity on GABA, 5-HT and Dopamine in albino rat brain

Endosulfan and its toxicity on GABA, 5-HT and Dopamine in albino rat brain

In vivo detection and automatic analysis of GABA in the mouse brain with MEGA-PRESS at 9.4T.

The goals of this study were to develop an acquisition protocol and the analysis tools for Meshcher-Garwood point-resolved spectroscopy (MEGA-PRESS) in mouse brain at 9.4T, to allow the in vivo detection of γ-aminobutyric acid (GABA) and to examine whether isoflurane alters GABA levels in the thalamus during anesthesia. We implemented the MEGA-PRESS sequence on a Bruker 94/20 system with ParaVision 6.0.1, and magnetic resonance spectra were acquired from nine male wild-type C57BL/6J mice at the thalamus. Four individual scans were obtained for each mouse in a 2-h time course whilst the mouse was anesthetized with isoflurane. We developed an automated analysis program with improved correction for frequency and phase drift compared with the standard creatine (Cr) fitting-based method and provided automatic quantification. During MEGA-PRESS acquisition, a single voxel with a size of 5×3×3mm3 was placed at the thalamus to evaluate GABA to Cr (GABA/Cr) ratios during anesthesia. Detection and quantitative analysis of thalamic GABA levels were successfully achieved. We noticed a significant decrease in GABA/Cr during the 2-h anesthesia (by linear regression analysis: slope<0, p<0.0001). In summary, our findings demonstrate that MEGA-PRESS is a feasible technique to measure in vivo GABA levels in the mouse brain at 9.4T.

Calcitonin potentiates the anticonvulsant and antinociceptive effects of valproic acid and pregabalin in pentylenetetrazole-kindled mice

Antiepileptic drugs are the backbone for epilepsy management. Epilepsy may be accompanied by decreased pain threshold. Thus, anticonvulsant agents with antinociceptive properties are of great importance. This study investigated the possible anticonvulsant and antinociceptive effects of calcitonin in combination with either valproic acid or pregabalin and whether these effects might occur through γ-aminobutyric acid (GABA) modulation.Eighty-four male Balb/C mice were divided into 7 groups: control-naïve, pentylenetetrazole (PTZ)-induced seizures, PTZ-calcitonin, PTZ-valproic acid, PTZ-pregabalin, PTZ-calcitonin-valproic acid (PCV) combination, and PTZ-calcitonin-pregabalin (PCP) combination. PTZ was used in a sub-convulsive dosage, every other day for 11 injections. Drugs were given i.p. 30min before PTZ. After each PTZ injection, mice were put under observation and PTZ-provoked seizures were assessed. After the last dose of PTZ, the hot plate test was used to assess antinociceptive properties. Also, brain GABA neurotransmitter was evaluated by immunoassay.Repeated injection of PTZ induced chemical kindling. Calcitonin was found to have significant antinociceptive property as shown by hot plate latency. The beneficial effects of PCV and PCP combination were statistically significant in epilepsy and pain models as compared to valproic acid and pregabalin. The antiepileptic and antinociceptive activity of calcitonin may not relate to the GABAergic system.Calcitonin enhanced the anticonvulsant and antinociceptive effects of either valproic acid or pregabalin. This new treatment “calcitonin add-on” may provide an improved range of options for patients with refractory epilepsy which is still an important risk factor for sudden death.

GABAergic Mechanisms in Schizophrenia: Linking Postmortem and In Vivo Studies.

Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, disorganized thinking, and impairments in cognitive functioning. Evidence from postmortem studies suggests that alterations in cortical γ-aminobutyric acid (GABAergic) neurons contribute to the clinical features of schizophrenia. In vivo measurement of brain GABA levels using magnetic resonance spectroscopy (MRS) offers the possibility to provide more insight into the relationship between problems in GABAergic neurotransmission and clinical symptoms of schizophrenia patients. This study reviews and links alterations in the GABA system in postmortem studies, animal models, and human studies in schizophrenia. Converging evidence implicates alterations in both presynaptic and postsynaptic components of GABAergic neurotransmission in schizophrenia, and GABA may thus play an important role in the pathophysiology of schizophrenia. MRS studies can provide direct insight into the GABAergic mechanisms underlying the development of schizophrenia as well as changes during its course.

Evidence for the involvement of the GABA-ergic pathway in the anticonvulsant activity of the roots bark aqueous extract of Anthocleista djalonensis A. Chev. (Loganiaceae).

The root bark of Anthocleista djalonensis A. Chev. (Loganiaceae) is widely used in traditional medicine in Northern Cameroon to treat epilepsy and related conditions, such as migraine, insomnia, dementia, anxiety, and mood disorders. To investigate the anticonvulsant effects and the possible mechanisms of this plant, an aqueous extract of Anthocleista djalonensis (AEAD) was evaluated by using animal models of bicuculline-, picrotoxin-, pilocarpine-, and pentylenetetrazole-induced convulsions. Their effects on brain γ-aminobutyric acid (GABA) concentration and GABA-T activity were also determined. This extract significantly protected mice against bicuculline-induced motor seizures. It provided 80% protection against picrotoxin-induced tonic-clonic seizures, and strongly antagonized convulsions induced by pilocarpine. AEAD also protected 100% of mice against pentylenetetrazole-induced seizures. Flumazenil, a central benzodiazepine receptor antagonist and FG7142, a partial inverse agonist in the benzodiazepine site of the GABAA receptor complex, were found to have an inhibitory effect on the anticonvulsant action of AEAD in pentylenetetrazole test. Finally, the brain GABA concentration was significantly increased and GABA-T activity was inhibited by AEAD. The effects of Anthocleista djalonensis suggested the presence of anticonvulsant properties that might involve an action on benzodiazepine and/or GABA sites in the GABAA receptor complex or by modulating GABA concentration in the central nervous system (CNS).

Anterior cingulate cortex \u03b3-aminobutyric acid deficits in youth with depression

Abnormally low γ-aminobutyric acid (GABA) levels have been consistently reported in adults with major depressive disorder (MDD). Our group extended this finding to adolescents, and documented that GABA deficits were associated with anhedonia. Here we aimed to confirm our prior finding of decreased brain GABA in youth with depression and explore its associations with clinical variables. Forty-four psychotropic medication-free youth with MDD and 36 healthy control (HC) participants (12–21 years) were studied. Participants represent a combined sample of 39 newly recruited youth (MDD=24) and 41 youth from our previously reported study (MDD=20). GABA levels and the combined resonances of glutamate and glutamine (Glx) were measured in vivo in the anterior cingulate cortex using proton magnetic resonance spectroscopy. Youth with depression exhibited significantly lower GABA levels than HC in both the newly reported (P=0.003) and the combined (P=0.003) samples. When depressed participants were classified based on the presence of anhedonia, only the anhedonic MDD subgroup showed reduced GABA levels compared to HC (P=0.002). While there were no associations between any clinical measures and GABA or Glx levels in the new sample, GABA was negatively correlated with only anhedonia severity in the combined MDD group. Furthermore, in the combined sample, hierarchical regression models showed that anhedonia, but not depression severity, anxiety or suicidality, contributed significant variance in GABA levels. This report solidifies the evidence for a GABA deficit early in the course of MDD, which correlates specifically with anhedonia in the disorder.

In Vivo Detection of CPP-115 Target Engagement in Human Brain

CPP-115, a next-generation γ-amino butyric acid (GABA)-aminotransferase (AT) inhibitor, shows comparable pharmacokinetics, improved safety and tolerability, and a more favorable toxicity profile when compared with vigabatrin. The pharmacodynamic characteristics of CPP-115 remain to be evaluated. The present study employed state-of-the-art proton magnetic resonance spectroscopy techniques to measure changes in brain GABA+ (the composite resonance of GABA, homocarnosine, and macromolecules) concentrations in healthy subjects receiving oral daily doses of CPP-115 or placebo. Six healthy adult males were randomized to receive either single daily 80 mg doses of CPP-115 (n=4) or placebo (n=2) for 6, 10, or 14 days. Metabolite-edited spectra and two-dimensional J-resolved spectroscopy data were acquired from the parietal-occipital cortex and supplementary motor area in all subjects. Four scans were performed in each subject that included a predrug baseline measure, two scans during the dosing timeframe, and a final scan that occurred 1 week after drug cessation. CPP-115 induced robust and significant increases in brain GABA+ concentrations that ranged between 52 and 141% higher than baseline values. Elevated GABA+ concentrations returned to baseline values following drug clearance. Subjects receiving placebo showed no significant changes in GABA+ concentration. CPP-115-induced changes were exclusive to GABA and homocarnosine, and CPP-115 afforded brain GABA+ concentration changes comparable to or greater than previous vigabatrin spectroscopy studies in healthy epilepsy-naive subjects. The return to baseline GABA+ concentration indicates the reversible GABA-AT resynthesis following drug washout. These preliminary data warrant further spectroscopy studies that characterize the acute pharmacodynamic effects of CPP-115 with additional dose-descending measures.

A GAB Aergic anxiolytic-like trait of thymoquinone, possibly via diazepam-co-agonistic pathway

This study evaluated the possible anxiolytic potential of thymoquinone (TQ), a promising component of Nigella sativa oil in male Swiss mice under unstressed and stressed conditions. A short-term physical stress (STPS) was produced by using an electric shaker. A new apparatus named as ‘swing apparatus’ was selected to carry out this study. TQ was tested at doses of 5, 10 and 20 mg/kg. In order to understand possible action mechanism, a GABA receptor agonist and an antagonist were used in this study. As agonist diazepam (DZP), while antagonist flumazenil (FZL) was used at 2 and 2.5 mg/kg doses. Treatments were given intraperitoneally. The brain GABA levels were determined by UV-spectrophotometric method. The results suggest that, TQ dose-dependently exerted a significant (p&lt;0.05) anxiolytic effect in rodents, which was confirmed by the calming effect of the experimental animals in comparison to the vehicles' NC, DZP and FZL groups. An augmentation of the movements of the animals was observed in STPS applied groups. GABA levels in the mouse brain were also found to link with the behavioral activity, where TQ co-treated with DZP augmented the calming effect by decreasing GABA levels, which was reversed by the FZL pre- and post-treated groups, demonstrating possible co-agonistic and antagonistic effects with DZP and FZL, respectively. Therefore, this study suggests an involvement of GABAergic, possibly DZP-co-agonistic anxiolytic-like effect of TQ.

S-nitrosylation of GAD65 is implicated in decreased GAD activity and oxygen-induced seizures.

Breathing oxygen at partial pressures ≥2.5 atmospheres absolute, which can occur in diving and hyperbaric oxygen (HBO2) therapy, can rapidly become toxic to the central nervous system (CNS). This neurotoxicity culminates in generalized EEG epileptiform discharges, tonic-clonic convulsions and ultimately death. Increased production of neuronal nitric oxide (NO) has been implicated in eliciting hyperoxic seizures by altering the equilibrium between glutamatergic and GABAergic synaptic transmission. Inhibition of glutamic acid decarboxylase (GAD) activity in HBO2 promotes this imbalance; however, the mechanisms by which this occurs is unknown. Therefore, we conducted a series of experiments using mice, a species that is highly susceptible to CNS oxygen toxicity, to explore the possibility that NO modulates GABA metabolism. Mice were exposed to 100% oxygen at 4 ATA for various durations, and brain GAD and GABA transaminase (GABA-T) activity, as well as S-nitrosylation of GAD65 and GAD67 were determined. HBO2 inhibited GAD activity by 50% and this was negatively correlated with S-nitrosylation of GAD65, whereas GABA-T activity and S-nitrosylation of GAD67 were unaltered. These results suggest a new mechanism by which NO alters GABA metabolism, leading to neuroexcitation and seizures in HBO2.

Developmental Changes in Expression of GABAA Receptor Subunits α1, α2, and α3 in the Pig Brain

GABA is a major neurotransmitter in the mammalian brain. In the mature brain GABA exerts inhibitory actions via the GABA_A receptor (GABA_AR); however, in the immature brain GABA provides much of the excitatory drive. We examined the expression of 3 predominant GABA_A α-subunit proteins in the pig brain at various pre- and postnatal ages. Brain tissue was collected from piglets born via caesarean section at preterm ages 91, 97, 100, and 104 days' gestational age (GA), at term equivalent (114 days' GA, caesarean section) and at term, postnatal day 0 (P0) (spontaneous delivery, term = 115 days). Tissue was obtained from piglets at P4 and P7. Adult tissue from sows was collected postmortem after caesarean section. In all cortical regions and basal ganglia (1) α₃ exhibited a significant increase in protein expression at 100 days' GA, (2) α₃ expression decreased with age after 100 days' GA, (3) α₁ increased with age, with peak expression at P7 in cortices, hippocampus, and thalamus, and (4) α₂ protein expression remained relatively constant across the ages examined. The subunit expression of α₃ was most abundant at preterm ages, with α₁ the predominant subunit expressed postnatally. Immunofluorescent labelling revealed α₁ expression on the somatic membranes of pyramidal cells in the cortex and hippocampus, and in the cerebellar Purkinje cells. Positive α₃ labelling was apparent on interneurones in the cortex and hippocampus. The switch between dominant α-subunits may coincide with the functional change in GABAergic neurotransmission from excitation to inhibition. Brain growth in the pig closely reflects that in the term human, making the pig a valuable non-primate model for studying development and the effects of insults on the perinatal brain.

Ameliorative potential of Colebrookea oppositifolia methanolic root extract against experimental models of epilepsy: Possible role of GABA mediated mechanism

BackgroundColebrookea oppositifolia Smith is one of the commonly used plants to treat epilepsy by various folk medicine communities like nomadic Gujjars, Tharu and Bhoxa in sub-Himalayan regions of India. PurposeThe present study was undertaken to evaluate the anticonvulsant activity of roots of Colebrookea oppositifolia using various experimental models of epilepsy in mice. MethodsPetroleum ether extract of roots of C. Oppositifolia (PeCO), methanolic eCO (MeCO) and aqueous eCO (AeCO) was initially evaluated in six-hertz-seizure test in mice, the effective extract was further evaluated against maximal electroshock (MES) and pentylenetetrazole (PTZ) models in mice. In addition, the potent extract was evaluated against the PTZ model by co-administering with flumazenil (FMZ), and also evaluated for its effect on brain GABA levels in brain and NMDA-induced lethality in mice. Furthermore, the possible locomotor deficit-inducing property of the extract was evaluated by actophotometer test in mice. ResultsIn six-hertz-seizure test the MeCO (25, 50, 100 and 200mg/kg) and AeCO (50, 100, 200, 400 and 800mg/kg) showed significant protection compared to control group, and MeCO was more potent than AeCO. Based on these outcomes, only MeCO was evaluated in MES and PTZ models. Notably, the MeCO (25, 50, 100 and 200mg/kg) has offered significant and dose- dependent protection against MES and PTZ-induced seizures in mice. Alongside, the MeCO (100 and 200mg/kg) showed a significant increase in GABA levels in the brain compared to control. In line with these findings, the anti-PTZ effect of MeCO (100mg/kg, p.o.) was blocked when co-administered with flumazenil (3mg/kg, i.p.),and in NMDA-induced mortality test, the MeCO has shown only 50% protection at 200mg/kg dose, thus confirmed the significant role of GABA pathway. Interestingly, the MeCO did not cause significant change in locomotor activity compared to before treatment. ConclusionThese findings suggest that MeCO possess significant anticonvulsant activity and the outcomes further confirmed the involvement of GABAergic mechanisms behind the anticonvulsant activity of MeCO.

Evaluation of anticonvulsant potential of aqueous methanolic extract and various fractions of Ajuga bracteosa wall

We aim to assess the anticonvulsant potential of Ajuga bracteosa Wall. The aqueous methanol extract (30:70) of Ajuga bracteosa and its n-hexane, chloroform and ethyl acetate fractions were prepared. Anticonvulsant effect was evaluated using different animal models of epilepsy. Crude extract along with its fractions at 500 and 1000 mg/kg doses, administered orally to albino mice were appraised against pentylenetetrazole-induced, strychnine-induced and picrotoxin-induced convulsions. Moreover, effect of test substances on brain GABA level and phenobarbitone induced hypnosis was also studied at dose level of 350 and 400 mg/kg. The plant extract and its fractions produced potent dose dependent anticonvulsant activity in all models of epilepsy. In addition, plant extract and fractions increased brain GABA level and potentiated phenobarbitone-induced sleep duration. From the results it can be deduced that Ajuga bracteosa possess potent anticonvulsant activity, supporting its folkloric use in the treatment of epilepsy.

Erratum to: Glutamate-glutamine and GABA in brain of normal aged and patients with cognitive impairment.

Erratum to: Glutamate-glutamine and GABA in brain of normal aged and patients with cognitive impairment.

Parallel changes in brain GABA levels, sleep and mood state during acute cocaine withdrawal: Predictors of “readiness for treatment”?

Parallel changes in brain GABA levels, sleep and mood state during acute cocaine withdrawal: Predictors of “readiness for treatment”?

Acute stress effects on GABA and glutamate levels in the prefrontal cortex: A 7T 1H magnetic resonance spectroscopy study.

There is ample evidence that the inhibitory GABA and the excitatory glutamate system are essential for an adequate response to stress. Both GABAergic and glutamatergic brain circuits modulate hypothalamus-pituitary-adrenal (HPA)-axis activity, and stress in turn affects glutamate and GABA levels in the rodent brain. However, studies examining stress-induced GABA and glutamate levels in the human brain are scarce. Therefore, we investigated the influence of acute psychosocial stress (using the Trier Social Stress Test) on glutamate and GABA levels in the medial prefrontal cortex of 29 healthy male individuals using 7 Tesla proton magnetic resonance spectroscopy. In vivo GABA and glutamate levels were measured before and 30 min after exposure to either the stress or the control condition. We found no associations between psychosocial stress or cortisol stress reactivity and changes over time in medial prefrontal glutamate and GABA levels. GABA and glutamate levels over time were significantly correlated in the control condition but not in the stress condition, suggesting that very subtle differential effects of stress on GABA and glutamate across individuals may occur. However, overall, acute psychosocial stress does not appear to affect in vivo medial prefrontal GABA and glutamate levels, at least this is not detectable with current practice 1H-MRS.

A Potential Magnetic Resonance Imaging Technique Based on Chemical Exchange Saturation Transfer for In Vivo γ-Aminobutyric Acid Imaging

PurposeWe developed a novel magnetic resonance imaging (MRI) technique based on chemical exchange saturation transfer (CEST) for GABA imaging and investigated the concentration-dependent CEST effect ofGABA in a rat model of brain tumor with blood—brain barrier (BBB) disruption.Materials and MethodsAll MRI studies were performed using a 7.0-T Agilent MRI scanner. Z-spectra for GABA were acquired at 7.0 T, 37°C, and a pH of 7.0 using varying B1 amplitudes. CEST images of phantoms with different concentrations of GABA solutions (pH, 7.0) and other metabolites (glutamine, myoinositol, creatinine, and choline) were collected to investigate the concentration-dependent CEST effect of GABA and the potential contribution from other brain metabolites. CEST maps for GABA in rat brains with tumors were collected at baseline and 50 min, 1.5 h, and 2.0 h after the injection of GABA solution.ResultsThe CEST effect of GABA was observed at approximately 2.75 parts per million(ppm) downfield from bulk water, and this effect increased with an increase in the B1 amplitude and remained steady after the B1 amplitude reached 6.0 μT (255 Hz). The CEST effect of GABA was proportional to the GABA concentration in vitro. CEST imaging of GABA in a rat brain with a tumor and compromised BBB showed a gradual increase in the CEST effect after GABA injection.ConclusionThe findings of this study demonstrate the feasibility and potential of CEST MRI with the optimal B1 amplitude, which exhibits excellent spatial and temporal resolutions, to map changes in GABA.

Reality of Inhibitory GABA in Neonatal Brain: Time to Rewrite the Textbooks?

The issue of GABA action in the developing brain has been debated for several years. The accepted axiom has been that, in neonatal brain, GABA exerts a mainly excitatory effect on the network, gradually switching to inhibitory action in the course of brain development ([Ben-Ari et al., 2007][1]).