GABAA Receptor Density Research Articles

PET imaging identifies anti-inflammatory effects of fluoxetine and a correlation of glucose metabolism during epileptogenesis with chronic seizure frequency

The serotonergic system has shown to be altered during epileptogenesis and in chronic epilepsy, making selective serotonin reuptake inhibitors interesting candidates for antiepileptogenic therapy. In this study, we aimed to evaluate disease-modifying effects of fluoxetine during experimental epileptogenesis.Status epilepticus (SE) was induced by lithium-pilocarpine, and female rats were treated either with vehicle or fluoxetine over 15 days. Animals were subjected to 18F-FDG (7 days post-SE), 18F-GE180 (15 days post-SE) and 18F-flumazenil positron emission tomography (PET, 21 days post-SE). Uptake (18F-FDG), volume of distribution (18F-GE180) and binding potential (18F-flumazenil) were calculated. In addition, hyperexcitability testing and video-EEG monitoring were performed.Fluoxetine treatment did not alter brain glucose metabolism. 18F-GE180 PET indicated lower neuroinflammation in the hippocampus of treated animals (−22.6%, p = 0.042), but no differences were found in GABAA receptor density. Video-EEG monitoring did not reveal a treatment effect on seizure frequency. However, independently of the treatment, hippocampal FDG uptake 7 days after SE correlated with seizure frequency during the chronic phase (r = −0.58; p = 0.015).Fluoxetine treatment exerted anti-inflammatory effects in rats during epileptogenesis. However, this effect did not alter disease outcome. Importantly, FDG-PET in early epileptogenesis showed biomarker potential as higher glucose metabolism correlated to lower seizure frequency in the chronic phase.

GABAergic inhibition shapes behavior and neural dynamics in human visual working memory.

Neuronal inhibition, primarily mediated by GABAergic neurotransmission, is crucial for brain development and healthy cognition. Gamma-aminobutyric acid concentration levels in sensory areas have been shown to correlate with hemodynamic and oscillatory neuronal responses. How these measures relate to one another during working memory, a higher-order cognitive process, is still poorly understood. We address this gap by collecting magnetoencephalography, functional magnetic resonance imaging, and Flumazenil positron emission tomography data within the same subject cohort using an n-back working-memory paradigm. By probing the relationship between GABAA receptor distribution, neural oscillations, and Blood Oxygen Level Dependent (BOLD) modulations, we found that GABAA receptor density in higher-order cortical areas predicted the reaction times on the working-memory task and correlated positively with the peak frequency of gamma power modulations and negatively with BOLD amplitude. These findings support and extend theories linking gamma oscillations and hemodynamic responses to gamma-aminobutyric acid neurotransmission and to the excitation-inhibition balance and cognitive performance in humans. Considering the small sample size of the study, future studies should test whether these findings also hold for other, larger cohorts as well as to examine in detail how the GABAergic system and neural fluctuations jointly support working-memory task performance.

Effects of Escitalopram on the Functional Neural Circuits in an Animal Model of Adolescent Depression.

Although escitalopram is known to be an effective drug for adult depression, its disease-modifying efficacy on adolescents remains controversial. The present study aimed to evaluate the therapeutic effect of escitalopram on behavioral aspects as well as functional neural circuits by means of positron emission tomography. To generate the animal models of depression, restraint stress was used during the peri-adolescent period (RS group). Thereafter, escitalopram was administered after the end of stress exposure (Tx group). We performed NeuroPET studies of glutamate, glutamate, GABA, and serotonin systems. The Tx group showed no body weight change compared to the RS group. In the behavioral tests, the Tx group also displayed the similar time spent in open arms and immobility time to those for RS. In the PET studies, brain uptake values for the Tx group revealed no significant differences in terms of glucose, GABAA, and 5-HT1A receptor densities, but lower mGluR5 PET uptake compared to the RS group. In the immunohistochemistry, the Tx group showed the significant loss of neuronal cells in the hippocampus compared to the RS group. The administration of escitalopram had no therapeutic effect on the adolescent depression.

Erbb4 Deletion From Inhibitory Interneurons Causes Psychosis-Relevant Neuroimaging Phenotypes.

Converging lines of evidence suggest that dysfunction of cortical GABAergic inhibitory interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and glutamatergic metabolite levels, and decreases in ligand binding to GABAA α5 receptors and to the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between inhibitory interneuron dysfunction and these neuroimaging readouts are yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal inhibitory interneurons leads to synaptic defects, and behavioral and cognitive phenotypes relevant to psychosis in mice. Here, we investigated how this inhibitory interneuron disruption affects hippocampal in vivo neuroimaging readouts. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n = 12) and their wild-type littermates (Erbb4F/F, n = 12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. Erbb4 mutant mice showed significantly elevated ventral hippccampus CBF and glutamine levels, and decreased SV2A density across hippocampus sub-regions compared to wild-type littermates. No significant GABAA receptor density differences were identified. These findings demonstrate that specific disruption of cortical inhibitory interneurons in mice recapitulate some of the key neuroimaging findings in patients with psychosis, and link inhibitory interneuron deficits to non-invasive measures of brain function and neurochemistry that can be used across species.

GABAA and NMDA receptor density alterations and their behavioral correlates in the gestational methylazoxymethanol acetate model for schizophrenia

Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine-system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAA and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of α5GABAA receptors (α5GABAAR), [3H]-flumazenil to quantify α1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. α5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 α5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of α5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.

Modelling the functional roles of synaptic and extra-synaptic γ-aminobutyric acid receptor dynamics in circadian timekeeping.

In the suprachiasmatic nucleus (SCN), γ-aminobutyric acid (GABA) is a primary neurotransmitter. GABA can signal through two types of GABAA receptor subunits, often referred to as synaptic GABAA (gamma subunit) and extra-synaptic GABAA (delta subunit). To test the functional roles of these distinct GABAA in regulating circadian rhythms, we developed a multicellular SCN model where we could separately compare the effects of manipulating GABA neurotransmitter or receptor dynamics. Our model predicted that blocking GABA signalling modestly increased synchrony among circadian cells, consistent with published SCN pharmacology. Conversely, the model predicted that lowering GABAA receptor density reduced firing rate, circadian cell fraction, amplitude and synchrony among individual neurons. When we tested these predictions, we found that the knockdown of delta GABAA reduced the amplitude and synchrony of clock gene expression among cells in SCN explants. The model further predicted that increasing gamma GABAA densities could enhance synchrony, as opposed to increasing delta GABAA densities. Overall, our model reveals how blocking GABAA receptors can modestly increase synchrony, while increasing the relative density of gamma over delta subunits can dramatically increase synchrony. We hypothesize that increased gamma GABAA density in the winter could underlie the tighter phase relationships among SCN cells.

Subchronic Administration of Noopept and Semax Peptides Increases the Density of Cortical GABAA-Receptors in the Brain of BALB/c Mice

Subchronic Administration of Noopept and Semax Peptides Increases the Density of Cortical GABAA-Receptors in the Brain of BALB/c Mice

GABAa receptor density alterations revealed in a mouse model of early moderate prenatal ethanol exposure using [18F]AH114726

IntroductionPrenatal ethanol exposure (PEE) has been shown to alter the level and function of receptors in the brain, one of which is GABAa receptors (GABAaR), the major inhibitory ligand gated ion channels that mediate neuronal inhibition. High dose PEE in animals resulted in the upregulation of GABAaR, but the effects of low and moderate dose PEE at early gestation have not been investigated. This study aimed at examining GABAaR density in the adult mouse brain following PEE during a period equivalent to the first 3 to 4 weeks in human gestation. It was hypothesized that early moderate PEE would cause alterations in brain GABAaR levels in the adult offspring. MethodsC57BL/6J mice were given 10% v/v ethanol during the first 8 gestational days. Male offspring were studied using in-vivo Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI), biodistribution, in-vitro autoradiography using [18F]AH114726, a novel flumazenil analogue with a high affinity for the benzodiazepine-binding site, and validated using immunohistochemistry. ResultsIn vivo PET and biodistribution did not detect alteration in brain tracer uptake. In vitro radiotracer studies detected significantly reduced GABAaR in the olfactory bulbs. Immunohistochemistry detected reduced GABAaR in the cerebral cortex, cerebellum and hippocampus, while Nissl staining showed that cell density was significantly higher in the striatum following PEE. ConclusionEarly moderate PEE may induce long-term alterations in the GABAaR system that persisted into adulthood.

A Multi-Ligand Imaging Study Exploring GABAergic Receptor Expression and Inflammation in Multiple Sclerosis.

The γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter and essential for normal brain function. The GABAergic system has been shown to have immunomodulatory effects and respond adaptively to excitatory toxicity. The association of the GABAergic system and inflammation in patients with multiple sclerosis (MS) remains unknown. In this pilot study, the in vivo relationship between GABAA binding and the innate immune response is explored using positron emission tomography (PET) with [11C] flumazenil (FMZ) and [11C]-PK11195 PET (PK-PET), a measure of activated microglia/macrophages. Sixteen MS patients had dynamic FMZ-PET and PK-PET imaging. Ten age-matched healthy controls (HC) had a single FMZ-PET. GABAA receptor binding was calculated using Logan reference model with the pons as reference. Distribution of volume ratio (VTr) for PK-PET was calculated using image-derived input function. A hierarchical linear model was fitted to assess the linear association between PK-PET and FMZ-PET among six cortical regions of interest. GABAA receptor binding was higher throughout the cortex in MS patients (5.72 ± 0.91) as compared with HC (4.70 ± 0.41) (p = 0.002). A significant correlation was found between FMZ binding and PK-PET within the cortex (r = 0.61, p < 0.001) and among the occipital (r = 0.61, p = 0.012), parietal (r = 0.49, p = 0.041), and cingulate (r = 0.32, p = 0.006) regions. A higher GABAA receptor density in MS subjects compared with HC was observed and correlated with innate immune activity. Our observations demonstrate that immune-driven GABAergic abnormalities may be present in MS.

Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger’s Diagnostic Scale–Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water’s relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

Activity of Energy Metabolism Enzymes and ATP Content in the Brain and Gills of the Black Sea Scorpionfish Scorpaena porcus under Short-Term Hypoxia

The effect of short-term hypoxia on the activity of oxidoreductases, malate dehydrogenase (MDH, 1.1.1.37) and lactate dehydrogenase (LDH, 1.1.1.27) responsible for urgent adaptation to oxygen deficiency, was studied in the brain and gills (first branchial arch) of the Black Sea scorpionfish Scorpaena porcus. The control group of fish was kept at 4.5–6.7 mg O2 L–1 (normoxia), experimental groups were exposed to 1.7–3.7 mg O2 L–1 (mild hypoxia) and 0.3–1.0 mg O2 L–1 (acute hypoxia); the exposure time was 90 min, water temperature 21–22°C. The dissolved oxygen level was reduced by saturating water with nitrogen. Hypoxia had no significant impact on the brain structures. Under acute hypoxia, MDH and LDH activities, the MDH/LDH index and ATP level in the forebrain, diencephalon and midbrain (FDMB), as well as in the medulla oblongata (MB), remained at the level of control values. Mild hypoxia caused a proportional rise in MDH and LDH activities and an increase in the ATP level in FDMB, most likely, due to a reduced demand for ATP in this brain region. This phenomenon is supposed to be based on the GABAergic mechanism of brain activity regulation, which is able to reduce energy demands of nervous tissue due to increasing the GABAA receptor density. The gills were distinguished by minimum MDH and LDH activities at the background of high MDH/LDH index values. Acute hypoxia led to decrease LDH activity and increase the MDH/LDH index in the gills, reflecting thereby a transition of this organ to an anaerobic operational mode. Under acute hypoxia, there was detected an increase in the relationship within the “MDH activity ↔ LDH activity” system in all types of tissues (r = 0.81–0.94, p < 0.05–0.01), which is typical of the species tolerant to oxygen deficiency. Apparently, this effect is based on MDH coupling with glycolytic substrates under conditions of acute oxygen deficiency, which rules out excessive lactate accumulation under metabolic depression.

Developmental Changes of Glutamate and GABA Receptor Densities in Wistar Rats.

Neurotransmitters and their receptors are key molecules of signal transduction and subject to various changes during pre- and postnatal development. Previous studies addressed ontogeny at the level of neurotransmitters and expression of neurotransmitter receptor subunits. However, developmental changes in receptor densities to this day are not well understood. Here, we analyzed developmental changes in excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) receptors in adjacent sections of the rat brain by means of quantitative in vitro receptor autoradiography. Receptor densities of the ionotropic glutamatergic receptors α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) as well as of the ionotropic GABAA and metabotropic GABAB receptors were investigated using specific high-affinity ligands. For each receptor binding site, significant density differences were demonstrated in the investigated regions of interest [olfactory bulb, striatum, hippocampus, and cerebellum] and developmental stages [postnatal day (P) 0, 10, 20, 30 and 90]. In particular, we showed that the glutamatergic and GABAergic receptor densities were already present between P0 and P10 in all regions of interest, which may indicate the early relevance of these receptors for brain development. A transient increase of glutamatergic receptor densities in the hippocampus was found, indicating their possible involvement in synaptic plasticity. We demonstrated a decline of NMDA receptor densities in the striatum and hippocampus from P30 to P90, which could be due to synapse elimination, a process that redefines neuronal networks in postnatal brains. Furthermore, the highest increase in GABAA receptor densities from P10 to P20 coincides with the developmental shift from excitatory to inhibitory GABA transmission. Moreover, the increase from P10 to P20 in GABAA receptor densities in the cerebellum corresponds to a point in time when functional GABAergic synapses are formed. Taken together, the present data reveal differential changes in glutamate and GABA receptor densities during postnatal rat brain development, which may contribute to their specific functions during ontogenesis, thus providing a deeper understanding of brain ontogenesis and receptor function.

Catatonia with GABAA receptor antibodies

A 22-year-old African woman developed acute behavioural change, against a background of sickle cell disease with strokes requiring a ventriculoperitoneal shunt. She alternated between mutism with prolonged staring and posturing,...

The Involvement of the Serotonin, Glutamate, and GABA Receptors in the Manifestation of the Antidepressant-Like Effect of Cycloprolylglycine

Abstract—We studied the effect of a 2-week administration of cycloprolylglycine peptide (CPG) (1 and 2 mg/kg/day, i.p.) on the binding characteristics of serotonin 5-HT2A-, NMDA-, metabotropic glutamate mGluII-, GABAA- and GABAB-receptors in the brain of inbred BALB/c mice in vitro and ex vivo. It was found that CPG at doses of 1 and 2 mg/kg/day reduces the density of 5-HT2A receptors in the striatum of mice by 24 and 28%, respectively. A decrease in the density of NMDA receptors in the hippocampus was observed only at a dose of 2 mg/kg/day; it was 22%. At the same time, there was an increase in the density of GABAA receptors in the frontal cortex at a dose of 1 mg/kg/day by 36% compared with the control. The 2-week administration of CPG at both doses did not affect Bmax of mGluII- and GABAB receptors, as well as Kd in all groups. In the in vitro radioligand assay, the CPG did not affect the specific binding of the labeled ligands of the studied receptors. These data indicate the functional involvement of 5-HT2A, NMDA, and GABAA receptors in the formation of the antidepressant-like effect of cycloprolylglycine in BALB/c mice for the first time.

Variability in the Drug Response of M4 Muscarinic Receptor Knockout Mice During Day and Night Time.

Mice are nocturnal animals. Surprisingly, the majority of physiological/pharmacological studies are performed in the morning, i.e., in the non-active phase of their diurnal cycle. We have shown recently that female (not male) mice lacking the M4 muscarinic receptors (MR, M4KO) did not differ substantially in locomotor activity from their wild-type counterparts (C57Bl/6Tac) during the inactive period. Increased locomotion has been shown in the active phase of their diurnal cycle. We compared the effects of scopolamine, oxotremorine, and cocaine on locomotor response, hypothermia and spontaneous behavior in the open field arena in the morning (9:00 AM) and in the evening (9:00 PM) in WT and in C57Bl/6NTac mice lacking the M4 MR. Furthermore, we also studied morning vs. evening densities of muscarinic, GABAA, D1-like, D2-like, NMDA and kainate receptors using autoradiography in the motor, somatosensory and visual cortex and in the striatum, thalamus, hippocampus, pons, and medulla oblongata. At 9:00 AM, scopolamine induced an increase in motor activity in WT and in M4KO, yet no significant increase was observed at 9:00 PM. Oxotremorine induced hypothermic effects in both WT and M4KO. Hypothermic effects were more evident in WT than in M4KO. Hypothermia in both cases was more pronounced at 9:00 AM than at 9:00 PM. Cocaine increased motor activity when compared to saline. There was no difference in behavior in the open field between WT and M4KO when tested at 9:00 AM; however, at 9:00 PM, activity of M4KO was doubled in comparison to that of WT. Both WT and KO animals spent less time climbing in their active phase. Autoradiography revealed no significant morning vs. evening difference. Altogether, our results indicate the necessity of comparing morning vs. evening drug effects

GABAA Receptor Density Is Not Altered by a Novel Herbal Anxiolytic Treatment.

Anxiety disorders are highly prevalent and considered a major public health concern worldwide. Current anxiolytics are of limited efficacy and associated with various side effects. Our novel herbal treatment (NHT), composed of four constituents, was shown to reduce anxiety-like behavior while precluding a common side effect caused by current anxiolytics, i.e., sexual dysfunction. Nevertheless, NHT's mechanism of action is yet to be determined. There is evidence that some medicinal herbs interact with the GABAergic system. Therefore, we aimed to examine whether NHT's anxiolytic-like effect is exerted by alterations in GABAA receptor density in the hippocampus, prefrontal cortex, and hypothalamus. The effects of 3-weeks treatment with NHT on anxiety-like behavior and locomotion were assessed using the elevated plus maze (EPM) and the open field test (OFT), respectively. Regional GABAA receptor levels were analyzed using [3H] RO15-1788 high-affinity binding assays. In stressed mice, NHT reduced anxiety-like behavior similarly to the benzodiazepine, clonazepam, while locomotion remained intact. Lack of changes or minor changes in regional GABAA receptor density in the brain were induced by NHT or clonazepam. In naive mice, performance in the EPM, locomotion and GABAA receptor densities were not altered by treatment with NHT or clonazepam. These findings support NHT as an efficacious and safe anxiolytic, although the GABAergic involvement remains to be further elucidated.

GABAA Receptor Availability Changes Underlie Symptoms in Isolated Cervical Dystonia.

GABAA receptor availability changes within sensorimotor regions have been reported in some isolated forms of dystonia. Whether similar abnormalities underlie symptoms in cervical dystonia is not known. In the present study, a total of 15 cervical dystonia patients and 15 age- and sex-matched controls underwent 11C-flumazenil PET/CT scanning. The density of available GABAA receptors was estimated using a Simplified Reference Tissue Model 2. Group differences were evaluated using a two-sample T-test, and correlations with dystonia severity, as measured by the Toronto Western Spasmodic Torticollis Rating Scale, and disease duration were evaluated using a regression analysis. Voxel-based analyses revealed increased GABAA availability within the right precentral gyrus in brain motor regions previously associated with head turning and the left parahippocampal gyrus. GABAA availability within the bilateral cerebellum was negatively correlated with dystonia severity, and GABAA availability within the right thalamus and a variety of cerebellar and cortical regions were negatively correlated with disease duration. While GABAA availability changes within primary motor areas could represent a partial compensatory response to loss of inhibition within sensorimotor network, GABAergic signaling impairment within the cerebellum may be a key contributor to dystonia severity.

Vascular-metabolic and GABAergic Inhibitory Correlates of Neural Variability Modulation. A Combined fMRI and PET Study

Neural activity varies continually from moment to moment. Such temporal variability (TV) has been highlighted as a functionally specific brain property playing a fundamental role in cognition. We sought to investigate the mechanisms involved in TV changes between two basic behavioral states, namely having the eyes open (EO) or eyes closed (EC) in vivo in humans. To these ends we acquired BOLD fMRI, ASL, and [18F]-fluoro-deoxyglucose PET in a group of healthy participants (n = 15), along with BOLD fMRI and [18F]-flumazenil PET in a separate group (n = 19). Focusing on an EO- vs EC-sensitive region in the occipital cortex (identified in an independent sample), we show that TV is constrained in the EO condition compared to EC. This reduction is correlated with an increase in energy consumption and with regional GABAA receptor density. This suggests that the modulation of TV by behavioral state involves an increase in overall neural activity that is related to an increased effect from GABAergic inhibition in addition to any excitatory changes. These findings contribute to our understanding of the mechanisms underlying activity variability in the human brain and its control.

Loss of inhibition in sensorimotor networks in focal hand dystonia.

ObjectiveTo investigate GABA-ergic receptor density and associated brain functional and grey matter changes in focal hand dystonia (FHD).Methods18 patients with FHD of the right hand and 18 age and gender matched healthy volunteers (HV) participated in this study. We measured the density of GABA-A receptors using [11C] Flumazenil and perfusion using [15O] H2O. Anatomical images were also used to measure grey matter volume with voxel-based morphometry (VBM).ResultsIn FHD patients compared to HV, the vermis VI of the right cerebellum and the left sensorimotor cortex had a decrease of Flumazenil binding potential (FMZ-BP), whereas the striatum and the lateral cerebellum did not show significant change. Bilateral inferior prefrontal cortex had increased FMZ-BP and an increase of perfusion, which correlated negatively with disease duration. Only the left sensorimotor cortex showed a decrease of grey matter volume.InterpretationImpairments of GABAergic neurotransmission in the cerebellum and the sensorimotor cortical areas could explain different aspects of loss of inhibitory control in FHD, the former being involved in maladaptive plasticity, the latter in surround inhibition. Reorganization of the inferior prefrontal cortices, part of the associative network, might be compensatory for the loss of inhibitory control in sensorimotor circuits. These findings suggest that cerebellar and cerebral GABAergic abnormalities could play a role in the functional imbalance of striato-cerebello-cortical loops in dystonia.

The role of glutamate and GABA receptors in the anticonvulsive effects of levetiracetam and a 4-phenylpirrolidone derivative (GIZh-290) in rats

The method of radioligand binding ex vivo has been used to evaluate the involvement of the ionotropic and metabotropic glutamate and GABA receptors in the mechanism of anticonvulsant action of levetiracetam and the original compound GIZh-290 (2-oxo-4-phenylpyrrolidin-1-yl) acetic acid) in the rat brain. We found that at the peak of lithium-pilocarpine seizures, the Bmax value (the density of specific binding sites) decreases for [3H]-SR 95531, [3H](–)baclofen, [3Н](+)MK-801, and [3H]LY 354740 by 30–50% from the control level. The pre-treatment with levetiracetam (600 mg/kg) 40 minutes before pilocarpine kept the number of GABA- and NMDA-type receptors at the control level without affecting the metabotropic receptors. The administration of GIZh-290 (5.0 mg/kg), in contrast, maintained the density of GABAA receptors at the control level, while the density of other types of receptors remained decreased at the peak of seizures. Thus, the anticonvulsant effect of levetiracetam and GIZh-290 has different mechanisms.