Modulation Of Gamma-aminobutyric Acid Research Articles

Increasing Ambient GABA Levels in the Hippocampus to Improve Cognition in a Mouse Model of Schizophrenia: A Research Protocol

Introduction: Schizophrenia is a complex psychiatric disorder characterized by cognitive, positive, and negative symptoms, with cognitive impairments significantly affecting learning, memory, and executive functions. The hippocampus, particularly the CA1 region, is a critical area of interest due to its role in learning and memory and its dysfunction in schizophrenia. This protocol explores the effects of increasing ambient Gamma-Aminobutyric Acid (GABA) levels in the CA1 region on cognitive functions in a Methylazoxymethanol Acetate (MAM) model of schizophrenia. Methods: Utilizing a two-by-two factorial design, male Sprague-Dawley rats undergo either a sham or MAM treatment, followed by a control or GABA modulation intervention. The study will employ GABA transporter inhibitor Tiagabine to increase ambient GABA levels and assess its impact on neuronal excitability and cognitive function. Behavioural assessments will include the Morris water maze and the Attentional set-shifting test to evaluate spatial memory and cognitive flexibility. Histological examinations and electrophysiological measurements will provide insights into structural and functional changes in the hippocampus. Results: The results are expected to demonstrate neurodevelopmental disruptions in MAM-treated offspring and improvements in cognitive performance following GABA modulation. Enhanced spatial memory and cognitive flexibility are anticipated in MAM-treated rats with GABA modulation, as evidenced by performance in the Morris water maze and Attentional set-shifting test. Electrophysiological recordings are likely to show increased tonic inhibition in the CA1 region. Discussion: This study aims to extend the understanding of tonic inhibition in schizophrenia treatment. By focusing on ambient GABA modulation, the research could offer novel insights into therapeutic strategies for schizophrenia, especially in enhancing cognitive functions. However, the translational applicability of intracerebral administration of uptake inhibitors like Tiagabine poses a significant challenge, highlighting the need for future research in more clinically viable methods of GABA modulation. Conclusion: This study was designed to contribute to schizophrenia research, particularly in understanding cognitive impairments and developing potential therapeutic strategies targeting the GABAergic system. The proposed findings could pave the way for novel treatments, improving the quality of life for individuals with schizophrenia.

Short chain fatty acid ameliorates hypothalamic apoptosis in a rat model of polycystic ovarian syndrome via modulation of gamma-aminobutyric acid

Short chain fatty acid ameliorates hypothalamic apoptosis in a rat model of polycystic ovarian syndrome via modulation of gamma-aminobutyric acid

Efficacy and role of essential oils as bio-insecticide against the pulse beetle Callosobruchus maculatus (F.) in post-harvest crops

Callosobruchus maculatus (Fab.) is considered as the most harmful pulse beetle attacking stored grains. Since synthetic pesticides have numerous disadvantages to human health and to the environment, essential oils (EOs) as a natural alternative can provide great efficiency against this pest. This review provides an outlook on published research and reports about the use of EOs against C. maculatus . The physiological aspects of C. maculatus , its life cycle and the grains host of this species were discussed. Moreover, the mechanism of action of EOs and the methods used to evaluate their insecticidal effect were also highlighted in this review. Medicinal plants have been used for their insecticidal activity and for pests’ management since ancient times, and nicotine was reported as the first insecticide from plants . The results revealed that the EOs from 121 species belonging to 26 family possess insecticidal effects against C. maculatus , with Lamiaceae (30 species) and Asteraceae (22 species) as the most representative. The major EOs constituents reported in this review, are mostly from terpenoids and sesquiterpenoids classes. Inhalation/fumigant toxicity, contact toxicity and repellency test were the most frequent methods used for the insecticidal activity. EOs have an inhibitory action on acetylcholinesterase (AChE), a role in the modulation of gamma-aminobutyric acid (GABA) receptors and an effect on octopaminergic receptors as main modes of actions. • Botanical products have been used in crop protection since ancient times. • Several methodologies of insecticidal effects have been reported in the literature. • The physiological aspect, life cycle, and distribution of C. maculatus are discussed in this review. • The EOs from 121 species belonging to 26 family possess insecticidal effects against C. maculatus. • Lamiaceae (30 species) and Asteraceae (22 species) are the most reported families.

From urges to tics in children with Tourette syndrome: associations with supplementary motor area GABA and right motor cortex physiology.

Tourette syndrome (TS) is a childhood-onset disorder in which tics are often preceded by premonitory sensory urges. More severe urges correlate with worse tics and can render behavioral therapies less effective. The supplementary motor area (SMA) is a prefrontal region believed to influence tic performance. To determine whether cortical physiological properties correlate with urges and tics, we evaluated, in 8-12-year-old right-handed TS children (n = 17), correlations of urge and tic severity scores and compared both to cortical excitability (CE) and short- and long-interval cortical inhibition (SICI and LICI) in both left and right M1. We also modeled these M1 transcranial magnetic stimulation measures with SMA gamma-amino butyric acid (GABA) levels in TS and typically developing control children (n = 16). Urge intensity correlated strongly with tic scores. More severe urges correlated with lower CE and less LICI in both right and left M1. Unexpectedly, in right M1, lower CE and less LICI correlated with less severe tics. We found that SMA GABA modulation of right, but not left, M1 CE and LICI differed in TS. We conclude that in young children with TS, lower right M1 CE and LICI, modulated by SMA GABA, may reflect compensatory mechanisms to diminish tics in response to premonitory urges.

GABAergic Modulation in Movement Related Oscillatory Activity: A Review of the Effect Pharmacologically and with Aging

Gamma-aminobutyric acid (GABA) is a ubiquitous inhibitory neurotransmitter critical to the control of movement both cortically and subcortically. Modulation of GABA can alter the characteristic rest as well as movement-related oscillatory activity in the alpha (8–12 Hz), beta (13–30 Hz, and gamma (60–90 Hz) frequencies, but the specific mechanisms by which GABAergic modulation can modify these well-described changes remains unclear. Through pharmacologic GABAergic modulation and evaluation across the age spectrum, the contributions of GABA to these characteristic oscillatory activities are beginning to be understood. Here, we review how baseline GABA signaling plays a key role in motor networks and in cortical oscillations detected by scalp electroencephalography and magnetoencephalography. We also discuss the data showing specific alterations to baseline movement related oscillatory changes from pharmacologic intervention on GABAergic tone as well as with healthy aging. These data provide greater insight into the physiology of movement and may help improve future development of novel therapeutics for patients who suffer from movement disorders.

A Review Focused on Molecular Mechanisms of Anxiolytic Effect of Valerina officinalis L. in Connection with Its Phytochemistry through in vitro/in vivo Studies.

Valeriana officinalis L. (Valerianaceae) is one of the most reputed ancient medicinal plants used in modern phytotherapy and traditional medicine. Its root extract is one of the most effective herbal sedatives and tranquilizers, where the plant is also used for the treatment of gastrointestinal spasms. V. officinalis has complex phytochemistry consisting of the esterified iridoid derivatives known as valepotriates (e.g., valtrate, didrovaltrate, isovalerenic acid), sesquiterpenes (e.g., valerenic acid), flavonoids (e.g., linarin, apigenin), lignans (e.g., pinoresinol, hydroxypinoresinol), alkaloids (e.g., actinidine, valerine), triterpenes (e.g., ursolic acid), monoterpenes (e.g., borneol, bornyl acetate). Among them, valerenic acid is a marker compound for standardization of the root extracts of the plant and has been reported in many in vitro/in vivo studies to be responsible for anxiolytic action of the plant. Although modulation of gamma-aminobutyric acid (GABA) receptors has been revealed to be the leading mechanism of the plant-based on the existence of valerenic acid, several studies described the interaction of valerenic acid with glutamergic receptors. In addition to valerenic acid, isovaleric acid, didrovaltrate, borneol, and some lignans have also been proposed to contribute to the anxiolytic effect of the plant. In the current review, the data selectively scrutinized from the in vitro/in vivo studies about identifying anxiolytic molecular mechanisms of V. officinalis is focused.

Environmental pharmaceuticals and climate change: The case study of carbamazepine in M. galloprovincialis under ocean acidification scenario

Contaminants of emerging concern and ocean changes are key environmental stressors for marine species with possibly synergistic, but still unexplored, deleterious effects. In the present study the influence of a simulated ocean acidification scenario (pH = 7.6) was investigated on metabolism and sub-lethal effects of carbamazepine, CBZ (1 µg/L), chosen as one of the most widely diffused pharmaceuticals in marine organisms. A multidisciplinary approach was applied on mussels, M. galloprovincialis, integrating measurement of drug bioaccumulation with changes in the whole transcriptome, responsiveness of various biochemical and cellular biomarkers including immunological parameters, lipid and oxidative metabolism, onset of genotoxic effects. Chemical analyses revealed a limited influence of hypercapnia on accumulation and excretion of CBZ, while a complex network of biological responses was observed in gene expression profile and functional changes at cellular level. The modulation of gamma-aminobutyric acid (GABA) pathway suggested similarities with the Mechanism of Action known for vertebrates: immune responses, cellular homeostasis and oxidative system represented the processes targeted by combined stressors. The overall elaboration of results through a quantitative Weight of Evidence model, revealed clearly increased cellular hazard due to interactions of CBZ with acidification compared to single stressors.

Multiple Sleep Latency Test/Maintenance of Wakefulness Test and Central Hypersomnias: Evolving Diagnostic and Therapeutic Approaches.

Central disorders of hypersomnolence include a spectrum of conditions, such as narcolepsy, idiopathic hypersomnia, and Kleine-Levin syndrome, in which excessive daytime sleepiness is the primary feature. Subjective testing with tools, such as sleep logs and sleepiness scales, are often helpful in the evaluation of these disorders but do not necessarily correlate well with objective testing, such as polysomnography and multiple sleep latency test and maintenance of wakefulness test. The most recent International Classification of Sleep Disorders-Third Edition has incorporated biomarkers, such as cerebrospinal fluid hypocretin level, into the diagnostic criteria and have restructured the classification of conditions based on our evolved understanding of their underlying pathophysiologic mechanisms. Therapeutic approaches largely consist of behavioral therapy, with a focus on optimizing sleep hygiene, optimizing opportunity for sleep, and strategic napping, along with judicious use of analeptic and anticataleptic agents when necessary. Emerging therapy has revolved around hypocretin-replacement therapy, immunotherapy, and nonhypocretin agents, with the goal of better targeting the underlying pathophysiology of these disorders rather than addressing symptoms. The most novel treatments have targeted the histaminergic system (pitolisant), dopamine reuptake transmission (solriamfetol), and gamma-aminobutyric acid modulation (flumazenil and clarithromycin) to promote wakefulness. Continued research is required for a more solid understanding of the biology of these conditions to develop a more robust armamentarium of therapeutic options.

Flexible Electrocorticography Electrode Array for Epileptiform Electrical Activity Recording under Glutamate and GABA Modulation on the Primary Somatosensory Cortex of Rats.

Epilepsy is a common neurological disorder. There is still a lack of methods to accurately detect cortical activity and locate lesions. In this work, a flexible electrocorticography (ECoG) electrode array based on polydimethylsiloxane (PDMS)-parylene was fabricated to detect epileptiform activity under glutamate (Glu) and gamma-aminobutyric acid (GABA) modulation on primary somatosensory cortex of rats. The electrode with a thickness of 20 μm has good flexibility to establish reliable contact with the cortex. Fourteen recording sites with a diameter of 60 μm are modified by electroplating platinum black nanoparticles, which effectively improve the performance with lower impedance, obtaining a sensitive sensing interface. The electrode enables real-time capturing changes in neural activity under drug modulation. Under Glu modulation, neuronal populations showed abnormal excitability, manifested as hypsarrhythmia rhythm and continuous or periodic spike wave epileptiform activity, with power increasing significantly. Under GABA modulation, the excitement was inhibited, with amplitude and power reduced to normal. The flexible ECoG electrode array could monitor cortical activity, providing us with an effective tool for further studying epilepsy and locating lesions.

The Delta-Subunit Selective GABA A Receptor Modulator, DS2, Improves Stroke Recovery via an Anti-inflammatory Mechanism.

Inflammatory processes are known to contribute to tissue damage in the central nervous system (CNS) across a broad range of neurological conditions, including stroke. Gamma amino butyric acid (GABA), the main inhibitory neurotransmitter in the CNS, has been implicated in modulating peripheral immune responses by acting on GABAA receptors on antigen-presenting cells and lymphocytes. Here, we investigated the effects and mechanism of action of the delta-selective compound, DS2, to improve stroke recovery and modulate inflammation. We report a decrease in nuclear factor (NF)-κB activation in innate immune cells over a concentration range in vitro. Following a photochemically induced motor cortex stroke, treatment with DS2 at 0.1 mg/kg from 1 h post-stroke significantly decreased circulating tumor necrosis factor (TNF)-α, interleukin (IL)-17, and IL-6 levels, reduced infarct size and improved motor function in mice. Free brain concentrations of DS2 were found to be lower than needed for robust modulation of central GABAA receptors and were not affected by the presence and absence of elacridar, an inhibitor of both P-glycoprotein and breast cancer resistance protein (BCRP). Finally, as DS2 appears to dampen peripheral immune activation and only shows limited brain exposure, we assessed the role of DS2 to promote functional recovery after stroke when administered from 3-days after the stroke. Treatment with DS2 from 3-days post-stroke improved motor function on the grid-walking, but not on the cylinder task. These data highlight the need to further develop subunit-selective compounds to better understand change in GABA receptor signaling pathways both centrally and peripherally. Importantly, we show that GABA compounds such as DS2 that only shows limited brain exposure can still afford significant protection and promote functional recovery most likely via modulation of peripheral immune cells and could be given as an adjunct treatment.

Challenges of simultaneous measurements of brain extracellular GABA and glutamate in vivo using enzyme-coated microelectrode arrays

BackgroundAlthough GABA is the major inhibitory neurotransmitter in the CNS, quantifying in vivo GABA levels has been challenging. The ability to co-monitor both GABA and the major excitatory neurotransmitter, glutamate, would be a powerful tool in both research and clinical settings. New methodCeramic-based microelectrode arrays (MEAs) were used to quantify gamma-aminobutyric acid (GABA) by employing a dual-enzyme reaction scheme including GABase and glutamate oxidase (GluOx). Glutamate was simultaneously quantified on adjacent recording sites coated with GluOx alone. Endogenous glutamate was subtracted from the combined GABA and glutamate signal to yield a pure GABA concentration. ResultsElectrode sensitivity to GABA in conventional, stirred in vitro calibrations at pH 7.4 did not match the in vivo sensitivity due to diffusional losses. Non-stirred calibrations in agarose or stirred calibrations at pH 8.6 were used to match the in vivo GABA sensitivity. In vivo data collected in the rat brain demonstrated feasibility of the GABA/glutamate MEA including uptake of locally applied GABA, KCl-evoked GABA release and modulation of endogenous GABA with vigabatrin. Comparison with existing methodsImplantable enzyme-coated microelectrode arrays have better temporal and spatial resolution than existing off-line methods. However, interpretation of results can be complicated due to the multiple recording site and dual enzyme approach. ConclusionsThe initial in vitro and in vivo studies supported that the new MEA configuration may be a viable platform for combined GABA and glutamate measures in the CNS extending the previous reports to in vivo GABA detection. The challenges of this approach are emphasized.

Tactile hypersensitivity and GABA concentration in the sensorimotor cortex of adults with autism.

Sensory hypersensitivity is frequently encountered in autism spectrum disorder (ASD). Gamma-aminobutyric acid (GABA) has been hypothesized to play a role in tactile hypersensitivity. The aim of the present study was twofold. First, as a study showed that children with ASD have decreased GABA concentrations in the sensorimotor cortex, we aimed at determining whether the GABA reduction remained in adults with ASD. For this purpose, we used magnetic resonance spectroscopy to measure GABA concentration in the sensorimotor cortex of neurotypical adults (n = 19) and ASD adults (n = 18). Second, we aimed at characterizing correlations between GABA concentration and tactile hypersensitivity in ASD. GABA concentration in the sensorimotor cortex of adults with ASD was lower than in neurotypical adults (decrease by 17%). Interestingly, GABA concentrations were positively correlated with self-reported tactile hypersensitivity in adults with ASD (r = 0.50, P = 0.01), but not in neurotypical adults. In addition, GABA concentrations were negatively correlated with the intra-individual variation during threshold measurement, both in neurotypical adults (r = -0.47, P = 0.04) and in adults with ASD (r = -0.59, P = 0.01). In other words, in both groups, the higher the GABA level, the more precise the tactile sensation. These results highlight the key role of GABA in tactile sensitivity, and suggest that atypical GABA modulation contributes to tactile hypersensitivity in ASD. We discuss the hypothesis that hypersensitivity in ASD could be due to suboptimal predictions about sensations. Autism Research 2019, 12: 562-575. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism spectrum disorder (ASD) often experience tactile hypersensitivity. Here, our goal was to highlight a link between tactile hypersensitivity and the concentration of gamma-aminobutyric acid (GABA) (an inhibitory neurotransmitter) in the brain of adults with ASD. Indeed, self-reported hypersensitivity correlated with reduced GABA levels in brain areas processing touch. Our study suggests that this neurotransmitter may play a key role in tactile hypersensitivity in autism.

Sex- and age-specific modulation of brain GABA levels in a mouse model of Alzheimer's disease

Age and sex are risk factors of Alzheimer's disease (AD). Among the neurotransmitter systems, gamma-aminobutyric acid (GABA) has been implicated in AD pathogenesis but the relevance of sex-specific GABAergic dysfunction during AD progression remains unknown. In the present study, we utilized state-of-the-art high-resolution magic angle spinning nuclear magnetic resonance to systematically monitor the brain region-, age-, and sex-specific modulation of GABA levels in wild-type and Tg2576 mice with amyloid pathology. In addition, we followed the possible role of reactive astrocytes in sex-specific GABA modulation. In female Tg2576 mice, hippocampal GABA levels were significantly elevated, along with higher number of reactive astrocytes and amyloid deposition. The elevated GABA was found to be produced via the monoamine oxidase-B route from putrescine in reactive astrocytes, more substantially in female than male mice, thus suggesting a role of astrocytes in memory impairment and sex-related differences in AD. Our results paint a coherent model of memory impairment in AD and signify that dynamic changes in regional GABA may be at the root of marked sex disparities observed in AD.

Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease.

Imbalance of gamma aminobutyric acid (GABA) and related modulators has been implicated as an important factor in the pathogenesis of amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND). In this context, the role and mechanism of action of gabapentin and baclofen have been extensively investigated, although with conflicting results. This is the first systematic review to assess clinical trials of GABA modulators for the treatment of ALS. To examine the efficacy of gabapentin, baclofen, or other GABA modulators in delaying the progression of ALS, and to evaluate adverse effects of these interventions On 16 August 2016, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, AMED, and LILACS. In addition, we checked the bibliographies of the trials found in order to identify any other trials, and contacted trial authors to identify relevant unpublished results or additional clinical trials. On 30 August 2016, we searched two clinical trials registries. Types of studies: double-blind randomized controlled trials (RCTs) or quasi-RCTsTypes of participants: adults with a diagnosis of probable or definite ALSTypes of interventions: gabapentin, baclofen, or other GABA modulators compared with placebo, no treatment, or each otherPrimary outcome: survival at one year from study enrollmentSecondary outcomes: individual rate of decline of maximum voluntary isometric contraction (MVIC), expressed as arm megascore; rate of decline of per cent predicted forced vital capacity (FVC); rate of decline of ALS Functional Rating Scale (ALSFRS); health-related quality of life; survival evaluated by pooling hazards; and adverse events DATA COLLECTION AND ANALYSIS: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies. At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies. We identified two double-blind RCTs of gabapentin treatment in ALS for inclusion in this review. We found no eligible RCTs of baclofen or other GABA modulators. The selected studies were phase II and phase III trials, which lasted six and nine months, respectively. They were highly comparable because both were comparisons of oral gabapentin and placebo, performed by the same investigators. The trials enrolled 355 participants with ALS: 80 in the gabapentin group and 72 in the placebo group in the first (phase II) trial and 101 in the gabapentin group and 102 in the placebo group in the second (phase III) trial. Neither trial was long enough to report survival at one year, which was our primary outcome. We found little or no difference in estimated one-year survival between the treated group and the placebo group (78% versus 77%, P = 0.63 by log-rank test; high-quality evidence). We also found little or no difference in the rate of decline of MVIC expressed as arm megascore, or rate of FVC decline (high-quality evidence). One trial investigated monthly decline in the ALSFRS and quality of life measured using the 12-Item Short Form Survey (SF-12) and found little or no difference between groups (moderate-quality evidence). The trials reported similar adverse events. Complaints that were clearly elevated in those taking gabapentin, based on analyses of the combined data, were light-headedness, drowsiness, and limb swelling (high-quality evidence). Fatigue and falls occurred more frequently with gabapentin than with placebo in one trial, but when we combined the data for fatigue from both trials, there was no clear difference between the groups. We assessed the overall risk of bias in the included trials as low. According to high-quality evidence, gabapentin is not effective in treating ALS. It does not extend survival, slow the rate of decline of muscle strength, respiratory function and, based on moderate-quality evidence, probably does not improve quality of life or slow monthly decline in the ALSFRS. Other GABA modulators have not been studied in randomized trials.

Segregation of Acetylcholine and GABA in the Rat Superior Cervical Ganglia: Functional Correlation.

Sympathetic neurons have the capability to segregate their neurotransmitters (NTs) and co-transmitters to separate varicosities of single axons; furthermore, in culture, these neurons can even segregate classical transmitters. In vivo sympathetic neurons employ acetylcholine (ACh) and other classical NTs such as gamma aminobutyric acid (GABA). Herein, we explore whether these neurons in vivo segregate these classical NTs in the superior cervical ganglia of the rat. We determined the topographical distribution of GABAergic varicosities, somatic GABAA receptor, as well as the regional distribution of the segregation of ACh and GABA. We evaluated possible regional differences in efficacy of ganglionic synaptic transmission, in the sensitivity of GABAA receptor to GABA and to the competitive antagonist picrotoxin (PTX). We found that sympathetic preganglionic neurons in vivo do segregate ACh and GABA. GABAergic varicosities and GABAA receptor expression showed a rostro-caudal gradient along ganglia; in contrast, segregation exhibited a caudo-rostral gradient. These uneven regional distributions in expression of GABA, GABAA receptors, and level of segregation correlate with stronger synaptic transmission found in the caudal region. Accordingly, GABAA receptors of rostral region showed larger sensitivity to GABA and PTX. These results suggest the presence of different types of GABAA receptors in each region that result in a different regional levels of endogenous GABA inhibition. Finally, we discuss a possible correlation of these different levels of GABA modulation and the function of the target organs innervated by rostral and caudal ganglionic neurons.

GABA-BZD Receptor Modulating Mechanism of Panax quinquefolius against 72-h Sleep Deprivation Induced Anxiety like Behavior: Possible Roles of Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation.

Rationale: Panax quinquefolius (American Ginseng) is known for its therapeutic potential against various neurological disorders, but its plausible mechanism of action still remains undeciphered. GABA (Gamma Amino Butyric Acid) plays an important role in sleep wake cycle homeostasis. Thus, there exists rationale in exploring the GABA-ergic potential of Panax quinquefolius as neuroprotective strategy in sleep deprivation induced secondary neurological problems.Objective: The present study was designed to explore the possible GABA-ergic mechanism in the neuro-protective effect of Panax quinquefolius against 72-h sleep deprivation induced anxiety like behavior, oxidative stress, mitochondrial dysfunction, HPA-axis activation and neuroinflammation.Materials and Methods: Male laca mice were sleep deprived for 72-h by using Grid suspended over water method. Panax quinquefolius (American Ginseng 50, 100, and 200 mg/kg) was administered alone and in combination with GABA modulators (GABA Cl− channel inhibitor, GABA-benzodiazepine receptor inhibitor and GABAA agonist) for 8 days, starting 5 days prior to 72-h sleep deprivation period. Various behavioral (locomotor activity, mirror chamber test), biochemical (lipid peroxidation, reduced glutathione, catalase, nitrite levels), mitochondrial complexes, neuroinflammation marker (Tumor Necrosis Factor, TNF-alpha), serum corticosterone, and histopathological sections of brains were assessed.Results: Seventy two hours sleep deprivation significantly impaired locomotor activity, caused anxiety-like behavior, conditions of oxidative stress, alterations in mitochondrial enzyme complex activities, raised serum corticosterone levels, brain TNFα levels and led to neuroinflammation like signs in discrete brain areas as compared to naive group. Panax quinquefolius (100 and 200 mg/kg) treatment restored the behavioral, biochemical, mitochondrial, molecular and histopathological alterations. Pre-treatment of GABA Cl− channel inhibitor as well as GABA-benzodiazepine receptor inhibitor, significantly reversed the protective effect of P. quinquefolius (100 mg/kg) in 72-h sleep deprived animals (P < 0.05). However, pretreatment with GABAA agonist, potentiated Panax quinquefolius's protective effect which was significant as compared to their effect per se (p < 0.05).Conclusion: GABA-ergic mechanism could be involved in the neuroprotective effect of P.quinquefolius against sleep deprivation induced anxiety-like behavior, oxidative stress, mitochondrial dysfunction, HPA axis activation and neuroinflammation.

The inhibition/excitation ratio related to task-induced oscillatory modulations during a working memory task: A multtimodal-imaging study using MEG and MRS

Detailed studies on the association between neural oscillations and the neurotransmitters gamma-aminobutyric acid (GABA) and glutamate have been performed in vitro. In addition, recent functional magnetic resonance imaging studies have characterized these neurotransmitters in task-induced deactivation processes during a working memory (WM) task. However, few studies have investigated the relationship between these neurotransmitters and task-induced oscillatory changes in the human brain. Here, using combined magnetoencephalography (MEG) and magnetic resonance spectroscopy (MRS), we investigated the modulation of GABA and glutamate + glutamine (Glx) concentrations related to task-induced oscillations in neural activity during a WM task. We first acquired resting-state MRS and MEG data from 20 healthy male volunteers using the n-back task. Time-frequency analysis was employed to determine the power induced during the encoding and retention phases in perigenual anterior cingulate cortex (pg-ACC), mid-ACC, and occipital cortex (OC). Statistical analysis showed that increased WM load was associated with task-induced oscillatory modulations (TIOMs) of the theta-gamma band relative to the zero-back condition (TIOM0B) in each volume of interest during the encoding phase of the n-back task. The task-induced oscillatory modulations in the two-back condition relative to the zero-back condition (TIOM2B-0B) were negatively correlated with the percent rate change of the correct hit rate for 2B-0B, but positively correlated with GABA/Glx. The positive correlation between TIOM2B-0B and GABA/Glx during the WM task indicates the importance of the inhibition/excitation ratio. In particular, a low inhibition/excitation ratio is essential for the efficient inhibition of irrelevant neural activity, thus producing precise task performance.

Effect of Withinia Somnifera and Shilajit on Alcohol Addiction in Mice.

Background:Alcohol addiction is a social problem leading to both loss of health and economic prosperity among addicted individuals. Common properties of anti-addictive compounds include anti-anxiety, anticonvulsants, anti-depressant, and nootropic actions primarily through modulation of gamma-aminobutyric acid (GABA) and serotonergic systems.Objective:Here, we screen ashwagandha and shilajit known ethnopharmacologically as nervine tonic and adaptogenic herbs for possible anti-addictive potential.Materials and Methods:Effect of ashwagandha churna and shilajit was measured on ethanol withdrawal anxiety using elevated plus maze. Role of ashwagandha and shilajit on chronic ethanol consumption (21 days) was measured using two bottle choice protocol of voluntary drinking. We also measured the effect of the above herbs on corticohippocampal GABA, dopamine, and serotonin levels.Results:Both ashwagandha and shilajit were found to reduce alcohol withdrawal anxiety in a dose-dependent manner. These herbs alone or in combination also decreased ethanol intake and increased water intake significantly after 21 days of chronic administration. Chronic administration of ashwagandha was found to significantly increase GABA and serotonin levels whereas shilajit altered cortico-hippocampal dopamine in mice.Conclusion:These central nervous system active herbs alone or in combination reduced both alcohol dependence and withdrawal thus showing promising anti-addictive potential.SUMMARY Withinia Somnifera alone and in combination with Shilajeet prevented ethanol withdrawal and alcohol addiction Abbreviations used: GABA: Gama aminobutyric acid, CNS: Central Nervous System, CPP:Condition place preference, DA: Dopamine, 5-HT: 5-hydroxytryptamine, NMDA:N-methyl-D-aspartate

GABA signalling modulates plant growth by directly regulating the activity of plant-specific anion transporters.

The non-protein amino acid, gamma-aminobutyric acid (GABA) rapidly accumulates in plant tissues in response to biotic and abiotic stress, and regulates plant growth. Until now it was not known whether GABA exerts its effects in plants through the regulation of carbon metabolism or via an unidentified signalling pathway. Here, we demonstrate that anion flux through plant aluminium-activated malate transporter (ALMT) proteins is activated by anions and negatively regulated by GABA. Site-directed mutagenesis of selected amino acids within ALMT proteins abolishes GABA efficacy but does not alter other transport properties. GABA modulation of ALMT activity results in altered root growth and altered root tolerance to alkaline pH, acid pH and aluminium ions. We propose that GABA exerts its multiple physiological effects in plants via ALMT, including the regulation of pollen tube and root growth, and that GABA can finally be considered a legitimate signalling molecule in both the plant and animal kingdoms.

Preterm birth affects GABAA receptor subunit mRNA levels during the foetal-to-neonatal transition in guinea pigs.

Modulation of gamma-aminobutyric acid A (GABAA) receptor signalling by the neurosteroid allopregnanolone has a major role in late gestation neurodevelopment. The objective of this study was to characterize the mRNA levels of GABAA receptor subunits (α4, α5, α6 and δ) that are key to neurosteroid binding in the brain, following preterm birth. Myelination, measured by the myelin basic protein immunostaining, was used to assess maturity of the preterm brains. Foetal guinea pig brains were obtained at 62 days' gestational age (GA, preterm) or at term (69 days). Neonates were delivered by caesarean section, at 62 days GA and term, and maintained until tissue collection at 24 h of age. Subunit mRNA levels were quantified by RT-PCR in the hippocampus and cerebellum of foetal and neonatal brains. Levels of the α6 and δ subunits were markedly lower in the cerebellum of preterm guinea pigs compared with term animals. Importantly, there was an increase in mRNA levels of these subunits during the foetal-to-neonatal transition at term, which was not seen following preterm birth. Myelination was lower in preterm neonatal brains, consistent with marked immaturity. Salivary cortisol concentrations, measured by EIA, were also higher for the preterm neonates, suggesting greater stress. We conclude that there is an adaptive increase in the levels of mRNA of the key GABAA receptor subunits involved in neurosteroid action after term birth, which may compensate for declining allopregnanolone levels. The lower levels of these subunits in preterm neonates may heighten the adverse effect of the premature decline in neurosteroid exposure.