Gamma-aminobutyric Acid System Research Articles

S58. Functional Characterization of Brain Organoids Derived From Human Pluripotent Stem Cells

Aberrant gamma-aminobutyric acid (GABA) system, the major inhibitory neurotransmitter in the CNS, is highly implicated in autism spectrum disorder (ASD). Development of the GABAergic neurons in human has only been recently examined, and the results unexpectedly show that GABA neurons are overproduced in ASD (Mariani et al 2015). It is essentially unknown as to how GABAergic transmission is perturbed in developing ASD circuitry.

GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia.

Schizophrenia is considered primarily as a cognitive disorder. However, functional outcomes in schizophrenia are limited by the lack of effective pharmacological and psychosocial interventions for cognitive impairment. GABA (gamma-aminobutyric acid) interneurons are the main inhibitory neurons in the central nervous system (CNS), and they play a critical role in a variety of pathophysiological processes including modulation of cortical and hippocampal neural circuitry and activity, cognitive function-related neural oscillations (eg, gamma oscillations) and information integration and processing. Dysfunctional GABA interneuron activity can disrupt the excitatory/inhibitory (E/I) balance in the cortex, which could represent a core pathophysiological mechanism underlying cognitive dysfunction in schizophrenia. Recent research suggests that selective modulation of the GABAergic system is a promising intervention for the treatment of schizophrenia-associated cognitive defects. In this review, we summarized evidence from postmortem and animal studies for abnormal GABAergic neurotransmission in schizophrenia, and how altered GABA interneurons could disrupt neuronal oscillations. Next, we systemically reviewed a variety of up-to-date subtype-selective agonists, antagonists, positive and negative allosteric modulators (including dual allosteric modulators) for α5/α3/α2 GABAA and GABAB receptors, and summarized their pro-cognitive effects in animal behavioral tests and clinical trials. Finally, we also discuss various representative histone deacetylases (HDAC) inhibitors that target GABA system through epigenetic modulations, GABA prodrug and presynaptic GABA transporter inhibitors. This review provides important information on current potential GABA-associated therapies and future insights for development of more effective treatments.

The neurochemical basis of the contextual interference effect.

Efficient practice organization maximizes learning outcome. Although randomization of practice as compared to blocked practice damages training performance, it boosts retention performance, an effect called contextual interference. Motor learning modulates the GABAergic (gamma-aminobutyric acid) system within the sensorimotor cortex (SM); however, it is unclear whether different practice regimes differentially modulate this system and whether this is impacted by aging. Young and older participants were trained on 3 variations of a visuomotor task over 3 days, following either blocked or random practice schedule and retested 6 days later. Using magnetic resonance spectroscopy, SM and occipital cortex GABA+ levels were measured before and after training during the first and last training days. We found that (1) behavioral data confirmed the contextual interference effects, (2) within-day occipital cortex GABA+ levels decreased in random and increased in blocked group. This effect was more pronounced in older adults; and (3) baseline SM GABA+ levels predicted initial performance. These findings indicate a differential modulation of GABA levels across practice groups that is amplified by aging.

Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology.

An expert review of the aetiology, assessment, and treatment of autism spectrum disorder, and recommendations for diagnosis, management and service provision was coordinated by the British Association for Psychopharmacology, and evidence graded. The aetiology of autism spectrum disorder involves genetic and environmental contributions, and implicates a number of brain systems, in particular the gamma-aminobutyric acid, serotonergic and glutamatergic systems. The presentation of autism spectrum disorder varies widely and co-occurring health problems (in particular epilepsy, sleep disorders, anxiety, depression, attention deficit/hyperactivity disorder and irritability) are common. We did not recommend the routine use of any pharmacological treatment for the core symptoms of autism spectrum disorder. In children, melatonin may be useful to treat sleep problems, dopamine blockers for irritability, and methylphenidate, atomoxetine and guanfacine for attention deficit/hyperactivity disorder. The evidence for use of medication in adults is limited and recommendations are largely based on extrapolations from studies in children and patients without autism spectrum disorder. We discuss the conditions for considering and evaluating a trial of medication treatment, when non-pharmacological interventions should be considered, and make recommendations on service delivery. Finally, we identify key gaps and limitations in the current evidence base and make recommendations for future research and the design of clinical trials.

GABA-modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence.

Anxiety disorders are chronic and functionally disabling conditions with high psychological stress, characterised by cognitive symptoms of excessive worry and focus difficulties and physiological symptoms such as muscle tension and insomnia. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter within the central nervous system and is a key target of pharmacotherapies in the treatment of anxiety. Although current pharmaceutical treatments are often efficacious, they may cause undesirable side effects including cognitive decrements and withdrawal symptoms. Plant-based "phytomedicines" may provide novel treatment options, to act as an adjunctive or alternative to existing anxiolytic medications. As such, we conducted a systematic review to assess the current body of literature on anxiolytic phytomedicines and/or phytoconstituents. An open-ended search to 5 July 2017 was conducted using MEDLINE (PubMed), Scopus, and Cochrane library online databases and performed in a stepped format from preclinical to clinical investigations. Eligible studies must have had (a) in vitro evidence of GABA-modulating activity, (b) animal studies using anxiety models to test an anxiolytic effect, and (c) human clinical trials. Ten phytomedicines were identified as having preclinical investigations showing interaction with the GABA system, in addition to human clinical trials: kava, valerian, pennywort, hops, chamomile, Ginkgo biloba, passionflower, ashwagandha, skullcap, and lemon balm. Collectively, the literature reveals preclinical and clinical evidence for various phytomedicines modulating GABA-pathways, with comparative anxiolytic effect to the current array of pharmaceuticals, along with good safety and tolerability profiles.

Very low doses of muscimol and baclofen ameliorate cognitive deficits and regulate protein expression in the brain of a rat model of streptozocin-induced Alzheimer's disease

Recent studies devoted to neuroprotection have focused on the role of the gamma-aminobutyric acid (GABA) system in regulating neuroinflammatory processes which play a key role in the neurodegenerative processes observed in Alzheimer's disease (AD) by inducing glial cell overactivation and impairing neurotransmission.Data on the efficacy of classical GABA-A and GABA-B receptor agonists (muscimol and baclofen, respectively) in animal models of AD are not available. Moreover, no published studies have examined the ability of optimal doses of these compounds to prevent neuroinflammation, the alterations in neurotransmission and cognitive deficits. In the present study, we used a non-transgenic rat model of AD obtained by intracerebroventricular streptozocin (STZ) injection and assessed the effects of muscimol and baclofen at very low doses (0.01–0.05mg/kg) on spatial memory and the expression of cortical and hippocampal proteins related to neuroinflammation, namely proteins involved in astroglial functions (glial fibrillary acidic protein, GFAP), GABA synthesis (GABA synthesizing enzyme, glutamic acid decarboxylase 67, GAD67) and acetylcholine degradation (acetylcholine esterase).The presented study demonstrated that in a rat model of STZ-induced AD both muscimol and baclofen at the tested doses exerted memory-enhancing and anti-inflammatory effects, as well as normalization of acetylcholine esterase and GABA expression. We suggested that the function of very low doses of GABA receptor agonists differs from typical GABA-related inhibition and may be mediated by the allosteric sites of GABA receptors or other non-specific cell regulatory pathways.

Restoration of autonomic balance and cortical and cerebral structures functions harmonization indicators by means of gamma-aminobutyric acid system modulation in patients with primary hypertension

The problem of arterial hypertension is getting more relevant because of the increasing of it prevalence both all over the world and inUkraine. Aim of the work was the investigation of psychoemotional disorders and vegetative homeostasis in patients with non-complicated forms of AH and their correction with the application of Passiflora incarnata extract as a part of the complex antihypertensive therapy. Materials and Methods. 73 patients of both sexes in active working age with AH stage II were examined. All patients were divided into 2 groups. Group 1 consisted of 35 patients with hypertension, who on the background of standard antihypertensive treatment were prescribed a plant remedy containing Passiflora incarnata extract – Alora® syrup (Nobelpharma Ilach Sanayi Wei Tidjaret A. Sh., Turkey) at a dose of 10 ml 3 times a day for 4 weeks. The 2 nd group was a control; it included 38 patients with hypertension treated only with antihypertensive therapy. pressure was measured with a manual mechanical tonometer at rest, according to the Unified clinical protocol of medical care Arterial hypertension. The psychoemotional state was investigated with the help of test questionnaire using the PHQ-90 Health Scale (maximum 27 points). To assess the state of autonomic regulation we used analysis of heart rate variability (HRV) values obtained with the IPEC-6-CARDIOPLUS FASAGRAF® device. Statistical processing was carried out using the Student's variation method. Results. The clinical study proves that using the medicine of Passiflora incarnata extract for patients with uncomplicated forms of hypertension during 4 weeks provides possibility to obtain an additional hypotensive effect against the background of using standard antihypertensive therapy as a demonstration of a wide range of Passiflora incarnata pharmacological activity. Conclusions. The implementation of the Рassiflora drug complex application are sympatholytic and vascular tone modifying effects, expressed positive dynamics in the psychoemotional state, manifested as anxiolytic and sedative actions, and optimization of the emotional state and degree of psychological tension in patients with AH.

Relationships between GAT1 and PTSD, Depression, and Substance Use Disorder.

Post-traumatic stress disorder (PTSD), Major Depressive Disorder (MDD), and Substance Use Disorder (SUD) have large public health impacts. Therefore, researchers have attempted to identify those at greatest risk for these phenotypes. PTSD, MDD, and SUD are in part genetically influenced. Additionally, genes in the glutamate and gamma-aminobutyric acid (GABA) system are implicated in the encoding of emotional and fear memories, and thus may impact these phenotypes. The current study examined the associations of single nucleotide polymorphisms in GAT1 individually, and at the gene level, using a principal components (PC) approach, with PTSD, PTSD comorbid with MDD, and PTSD comorbid with SUD in 486 combat-exposed veterans. Findings indicate that several GAT1 SNPs, as well as one of the GAT1 PCs, was associated with PTSD, with and without MDD and SUD comorbidity. The present study findings provide initial insights into one pathway by which shared genetic risk influences PTSD-MDD and PTSD-SUD comorbidities, and thus identify a high-risk group (based on genotype) on whom prevention and intervention efforts should be focused.

Role of gamma-aminobutyric acid ergic activation in pathology of −dopamine-2 receptors model of Parkinsonism in mice

BACKGROUND: Blocking of dopamine-2 receptors (D2R) in the brain showed motor symptoms seen in Parkinsonism. Since D2R is excitatory in the brain and blocking it is like inhibition. This work is designed to show if activating gamma aminobutyric acid (GABA) system in the brain contributes to the pathogenesis of Parkinsonism seen in–D2R model of Parkinsonism. MATERIALS AND METHODS: Twenty male adult albino mice were randomly divided into four groups (Veh, −D2R, +GABA, and −D2R + GABA). Veh. animals were given 0.04 mL of normal saline, −D2R were given 10 mg/kg body weight (BW) of haloperidol for 14 days, +GABA were given 10 mg/kg BW of diazepam for 7 days and −D2R + GABA were given 10 mg/kg BW of haloperidol for 14 days with subsequent 10 mg/kg BW of diazepam for 7 days. Each group contains 5 animals and all treatment was done intraperitoneally. Motor activity of the animals was assessed using rotarod, Y-maze for spatial memory and elevated plus maze for anxiety and locomotion. At the end of treatment, the animals were anesthetized using ketamine and perfused transcardially with formal saline. Brains were then excised and fixed in formal saline. The prefrontal cortex (PFC) and hippocampus were processed for histological study using hematoxylin and eosin stain and immunohistochemistry for Lewy bodies. Data were expressed as mean ± standard error of mean and analyzed using analysis of variance with Tukey post hoc test significant level was set at P RESULTS: Motor activity was significantly reduced in all treated groups (−D2R, +GABA and −D2R/+GABA) compared to the control (Veh) as they all have lower latency of fall and arm entries. Y-maze result shows that spatial memory was significantly reduced in –D2R and −D2R/+GABA groups but not + GABA. Anxiety-related behavior was high in all treated groups compared to control. Cellular distortion was observed in the PFC and hippocampus of all treated groups with −D2R/+GABA group having a high level of distortion. Lewy bodies accumulation was absent in the brain regions observed from all the groups. CONCLUSIONS: GABAergic activation aids motor and memory deficit and marked brain pathology in −D2R model of Parkinsonism.

Increased GABAA receptor binding in amygdala after prenatal administration of valproic acid to rats.

Prenatal exposure to valproic acid (VPA) enhances the risk for later development of autism spectrum disorders (ASD). An altered gamma-aminobutyric acid (GABA) system may be a key factor in ASD. Here we investigated possible changes in the GABA system in rats exposed to a low dose of prenatal VPA. We performed autoradiography with [3H]muscimol, (a GABAA receptor agonist), and [11C]Ro15-4513 (a partial agonist of the GABAA α1+5 receptor subtypes), in brain sections containing amygdala, thalamus and hippocampus of rats treated prenatally with 20 mg/kg VPA or saline from the 12th day of gestation. Result Prenatal VPA significantly increased [11C]Ro15-4513 binding in the left amygdala compared with controls (p<0.05). This difference was not observed in the hippocampus, thalamus or right amygdala. No differences were observed in [3H]muscimol binding. We observed an asymmetric increase in GABAA receptor binding. Disturbances in the GABAA receptor system have also been detected in human autism with [11C]Ro15-4513.

Renal Denervation Improves the Baroreflex and GABA System in Chronic Kidney Disease-induced Hypertension.

Hypertensive rats with chronic kidney disease (CKD) exhibit enhanced gamma-aminobutyric acid (GABA)B receptor function and regulation within the nucleus tractus solitarii (NTS). For CKD with hypertension, renal denervation (RD) interrupts the afferent renal sympathetic nerves, which are connecting to the NTS. The objective of the present study was to investigate how RD improves CKD-induced hypertension. Rats underwent 5/6 nephrectomy for 8 weeks, which induced CKD and hypertension. RD was induced by applying phenol to surround the renal artery in CKD. RD improved blood pressure (BP) by lowering sympathetic nerve activity and markedly restored the baroreflex response in CKD. The GABAB receptor expression was increased in the NTS of CKD; moreover, the central GABA levels were reduced in the cerebrospinal fluid, and the peripheral GABA levels were increased in the serum. RD restored the glutamic acid decarboxylase activity in the NTS in CKD, similar to the effect observed for central treatment with baclofen, and the systemic administration of gabapentin reduced BP. RD slightly improved renal function and cardiac load in CKD. RD may improve CKD-induced hypertension by modulating the baroreflex response, improving GABA system dysfunction and preventing the development and reducing the severity of cardiorenal syndrome type 4 in CKD rats.

Effects of high-dose ethanol intoxication and hangover on cognitive flexibility.

The effects of high-dose ethanol intoxication on cognitive flexibility processes are not well understood, and processes related to hangover after intoxication have remained even more elusive. Similarly, it is unknown in how far the complexity of cognitive flexibility processes is affected by intoxication and hangover effects. We performed a neurophysiological study applying high density electroencephalography (EEG) recording to analyze event-related potentials (ERPs) and perform source localization in a task switching paradigm which varied the complexity of task switching by means of memory demands. The results show that high-dose ethanol intoxication only affects task switching (i.e. cognitive flexibility processes) when memory processes are required to control task switching mechanisms, suggesting that even high doses of ethanol compromise cognitive processes when they are highly demanding. The EEG and source localization data show that these effects unfold by modulating response selection processes in the anterior cingulate cortex. Perceptual and attentional selection processes as well as working memory processes were only unspecifically modulated. In all subprocesses examined, there were no differences between the sober and hangover states, thus suggesting a fast recovery of cognitive flexibility after high-dose ethanol intoxication. We assume that the gamma-aminobutyric acid (GABAergic) system accounts for the observed effects, while they can hardly be explained by the dopaminergic system.

Altered expression of KCC2 in GABAergic interneuron contributes prenatal stress-induced epileptic spasms in infant rat

Long-term stress during pregnancy causes neurologic deficits to offspring with altered gamma-aminobutyric acid (GABA) system in the brain. However, it is not clear how prenatal stress affects the maturing GABAergic interneurons and the resulting abnormalities in infantile seizures. Here, we showed that prenatal stress alters the maturation of GABA inhibitory system using a seizure model induced by prenatal stress. Prenatal stress with betamethasone or acute immobilization stress (AIS) on gestational day 15 increased the seizure susceptibility to N-methyl-d-aspartate-triggered spasms on postnatal day 15. The expression of GABA was lower in the prenatally stressed group, which compromise the decrease of glutamate decarboxylase 67-immunopositive cells. Prenatal stress markedly decreased the expression of K+/Cl− co-transporter (KCC2) in the cortex. GABA induced membrane depolarization demonstrated prenatal stress models had significant higher membrane depolarization compared to control. GABA increased KCC2 expression in cultured cortex-containing slices. Taken together, our results showed that prenatal stress with betamethasone or AIS altered the maturation of GABAergic progenitors and resulted in the lack of GABA input, which in turn, decreased KCC2 expression and lowered seizure threshold. We conclude that delayed GABA excitatory/inhibitory shift would render the cortical neuronal circuit more susceptible to excitatory input in prenatal stress induced seizure.

Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies.

The inhibitory gamma-aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy ((1) H-MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical (1) H-MRS literature and performed a meta-analysis. A total of 40 studies (N = 1,591) in seven different psychiatric disorders were included in the meta-analysis: MDD (N = 437), schizophrenia (N = 517), ASD (N = 150), bipolar disorder (N = 129), panic disorder (N = 81), posttraumatic stress disorder (PTSD) (N = 104), and attention deficit/hyperactivity disorder (ADHD) (N = 173). Brain GABA levels were lower in ASD (standardized mean difference [SMD] = -0.74, P = 0.001) and in depressed MDD patients (SMD = -0.52, P = 0.005), but not in remitted MDD patients (SMD = -0.24, P = 0.310) compared with controls. In schizophrenia this finding did not reach statistical significance (SMD = -0.23, P = 0.089). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta-analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future (1) H-MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that (1) H-MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders. Hum Brain Mapp 37:3337-3352, 2016. © 2016 Wiley Periodicals, Inc.

Contribution of NMDA, GABAA and GABAB receptors and l-arginine-NO-cGMP, MEK1/2 and CaMK-II pathways in the antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in mice

It has been reported that the antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) may result from the modulation of brain monoaminergic systems. However, the mechanisms of FDPI action are not fully understood. The aim of this study was to investigate the contribution of N-methyl-d-aspartate (NMDA) and gamma-aminobutyric acid (GABA) systems as well as l-arginine-nitric oxide-(NO)-cyclic guanosine monophosphate-(cGMP), mitogen-activated protein/extracellular signal-regulated kinase (MEK1/2) and Ca2+/calmodulin-dependent protein kinase II (CaMK-II) signaling pathways in the antidepressant-like effect of FDPI in the mouse forced swimming test (FST). The levels of NO and uptake of [3H]glutamate and [3H]GABA were determined in prefrontal cortices of Swiss mice. Pretreatments with NMDA (0.1 pmol/site, i.c.v., a NMDA receptor agonist), bicuculline (1mg/kg, i.p., a GABAA receptor antagonist), phaclofen (2mg/kg, i.p., a GABAB receptor antagonist) and l-arginine (750mg/kg, i.p., a NO precursor), KN-62 (1μg/site, a CaMK-II inhibitor), U0126 (5μg/site, a MEK1/2 inhibitor) and PD09058 (5μg/site, a MEK1/2 inhibitor) blocked the antidepressant-like effect of FDPI, at a dose of 1mg/kg, in the FST. ODQ (30 pmol/site, i.c.v., a soluble guanylate cyclase (sGC) inhibitor) in combination with a sub-effective dose of FDPI (0.1mg/kg, i.g.) reduced the immobility time in the FST. The administration of FDPI (50mg/kg) to mice increased the glutamate uptake and reduced NO levels in the prefrontal cortex of mice. The results suggest a contribution of NMDA, GABAA and GABAB receptors and l-arginine-NO-cGMP pathway in the antidepressant-like action of FDPI in mice, and this effect is related to CaMK-II and MEK 1/2 activation.

A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder

Gamma-amino butyric acid (GABA) and glutamate are the major inhibitory and excitatory neurotransmitters in the mammalian central nervous system, respectively, and have been associated with suicidal behavior and major depressive disorder (MDD). We examined the relationship between genotype, brain transcriptome, and MDD/suicide for 24 genes involved in GABAergic and glutamatergic signaling. In part 1 of the study, 119 candidate SNPs in 24 genes (4 transporters, 4 enzymes, and 16 receptors) were tested for associations with MDD and suicidal behavior in 276 live participants (86 nonfatal suicide attempters with MDD and 190 non-attempters of whom 70% had MDD) and 209 postmortem cases (121 suicide deaths of whom 62% had MDD and 88 sudden death from other causes of whom 11% had MDD) using logistic regression adjusting for sex and age. In part 2, RNA-seq was used to assay isoform-level expression in dorsolateral prefrontal cortex of 59 postmortem samples (21 with MDD and suicide, 9 MDD without suicide, and 29 sudden death non-suicides and no psychiatric illness) using robust regression adjusting for sex, age, and RIN score. In part 3, SNPs with subthreshold (uncorrected) significance levels below 0.05 for an association with suicidal behavior and/or MDD in part 1 were tested for eQTL effects in prefrontal cortex using the Brain eQTL Almanac (www.braineac.org). No SNPs or transcripts were significant after adjustment for multiple comparisons. However, a protein coding transcript (ENST00000414552) of the GABA A receptor, gamma 2 (GABRG2) had lower brain expression postmortem in suicide (P = 0.01) and evidence for association with suicide death (P = 0.03) in a SNP that may be an eQTL in prefrontal cortex (rs424740, P = 0.02). These preliminary results implicate GABRG2 in suicide and warrant further investigation and replication in larger samples.

Neurobiology of Alcohol Dependence and Implications on Treatment

The process of alcohol dependence has been conceptualized as a progress from controlled alcohol intake to compulsive alcohol consumption or a shift from alcohol intake for pleasure to compulsory alcohol seeking behavior. Hereditary and physical factors and the interaction of individuals with their environment, as well as permanent changes in the neurotransmitter and neurohormonal systems in the brain due to alcohol use, play the most important role in the etiology of alcohol dependence. The effects of ethanol on the neurotransmitter, neuropeptide and neuroendocrine systems not only account for its acute physiological and euphoric/reinforcing effects but also seem to be responsible for the development of dependence. While the motivation for alcohol use is mainly positive reinforcement in the earlier phases of alcohol consumption, both positive and negative reinforcements are involved in the process once dependence has developed. This event is caused by neuroadaptive process due to chronic alcohol consumption and also called as "allostasis". It seems that the most important neuroadaptive changes in progression from occasional alcohol intake to dependence are the down-regulation of the dopamine and gamma aminobutyric acid systems, permanent upregulation in the glutamate system and dysregulation in the stress systems (corticotropin-releasing hormone and serotonin) of the brain. In this paper, we will review the adaptive changes caused by chronic alcohol consumption which are important in the development of dependence and address the potential therapeutic contributions of interventions to these changes in alcohol dependence.

Comparison of mirtazapine, gabapentin and ondansetron to prevent intrathecal morphine-induced pruritus.

OBJECTIVE:Antagonism of the central nervous system inhibitor neurotransmitter gamma-Aminobutyric acid (GABA) or serotonergic system activation is an important factor in the pathogenesis of intrathecal morphine-induced pruritus. This study tested the hypothesis that preoperative use of ondansetron, gabapentin or mirtazapine can prevent morphine-induced pruritus.METHODS:We randomly allocated 80 patients of American Society of Anesthesiology (ASA) classification I and II physical status who were to undergo unilateral inguinal hernia or pilonidal sinus operations under spinal anesthesia into 4 equal groups. The first 3 groups received oral doses of 30 mg mirtazapine, 8 mg ondansetron, and 1200 mg gabapentin at 2 hours, 10 minutes, and 1 hour before surgery, respectively, and the fourth group was given a placebo. All patients received intrathecal injection of 15 mg of 0.5% hyperbaric bupivacaine and 0.2 mg morphine. Pruritus was evaluated at 0, 3, 6, 9, 12, and 24 hours after intrathecal morphine administration, and details of presence, onset time, duration, localization, and severity of pruritus were recorded.RESULTS:Incidence of pruritus was significantly more frequent in the placebo group compared to ondansetron, gabapentin, and mirtazapine groups (70%, 55%, 35%, and 35%, respectively). In general, onset of pruritus was between 2 and 6 hours after intrathecal morphine injection; however, onset in the gabapentin group (mean±SD: 4.75±2.7 hours; p=0.019) was delayed compared to other groups. It was observed that pruritus persisted relatively longer in the ondansetron and placebo groups (mean±SD: 6±3.08; 5.82±2.96 hours, respectively; p=0.047). No statistical determination was made regarding location of pruritus. Severity of pruritus was greater in the placebo group (p=0.0001). Necessity for antipruritic treatment was not statistically significantly different between groups.CONCLUSION:Incidence and severity of intrathecal morphine-induced pruritus decreased with use of each of all 3 drugs compared to placebo.

GABA concentration in superior temporal sulcus predicts gamma power and perception in the sound-induced flash illusion

In everyday life we are confronted with inputs of multisensory stimuli that need to be integrated across our senses. Individuals vary considerably in how they integrate multisensory information, yet the neurochemical foundations underlying this variability are not well understood. Neural oscillations, especially in the gamma band (>30Hz) play an important role in multisensory processing. Furthermore, gamma-aminobutyric acid (GABA) neurotransmission contributes to the generation of gamma band oscillations (GBO), which can be sustained by activation of metabotropic glutamate receptors. Hence, differences in the GABA and glutamate systems might contribute to individual differences in multisensory processing. In this combined magnetic resonance spectroscopy and electroencephalography study, we examined the relationships between GABA and glutamate concentrations in the superior temporal sulcus (STS), source localized GBO, and illusion rate in the sound-induced flash illusion (SIFI). In 39 human volunteers we found robust relationships between GABA concentration, GBO power, and the SIFI perception rate (r-values=0.44 to 0.53). The correlation between GBO power and SIFI perception rate was about twofold higher when the modulating influence of the GABA level was included in the analysis as compared to when it was excluded. No significant effects were obtained for glutamate concentration. Our study suggests that the GABA level shapes individual differences in audiovisual perception through its modulating influence on GBO. GABA neurotransmission could be a promising target for treatment interventions of multisensory processing deficits in clinical populations, such as schizophrenia or autism.

Abnormal GABAergic function and face processing in schizophrenia: A pharmacologic-fMRI study

The involvement of the gamma-aminobutyric acid (GABA) system in schizophrenia is suggested by postmortem studies and the common use of GABA receptor-potentiating agents in treatment. In a recent study, we used a benzodiazepine challenge to demonstrate abnormal GABAergic function during processing of negative visual stimuli in schizophrenia. This study extended this investigation by mapping GABAergic mechanisms associated with face processing and social appraisal in schizophrenia using a benzodiazepine challenge. Fourteen stable, medicated schizophrenia/schizoaffective patients (SZ) and 13 healthy controls (HC) underwent functional MRI using the blood oxygenation level-dependent (BOLD) technique while they performed the Socio-emotional Preference Task (SePT) on emotional face stimuli (“Do you like this face?”). Participants received single-blinded intravenous saline and lorazepam (LRZ) in two separate sessions separated by 1–3weeks. Both SZ and HC recruited medial prefrontal cortex/anterior cingulate during the SePT, relative to gender identification. A significant drug by group interaction was observed in the medial occipital cortex, such that SZ showed increased BOLD signal to LRZ challenge, while HC showed an expected decrease of signal; the interaction did not vary by task. The altered BOLD response to LRZ challenge in SZ was significantly correlated with increased negative affect across multiple measures. The altered response to LRZ challenge suggests that abnormal face processing and negative affect in SZ are associated with altered GABAergic function in the visual cortex, underscoring the role of impaired visual processing in socio-emotional deficits in schizophrenia.