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Glutamatergic System (glutamatergic + system)
Selected AbstractsDifferential Adaptations in GABAergic and Glutamatergic Systems During Ethanol Withdrawal in Male and Female RatsALCOHOLISM, Issue 6 2005P E. Alele Background: There are significant and consistent sex differences in recovery from ethanol withdrawal in our animal model of ethanol dependence. We have also observed significant and varied sex differences in subunit protein levels of ,-aminobutyric acid A (GABAA) and the N-metheyl-D-aspartate subtype of glutamate receptors occurring with ethanol dependence and withdrawal. Considering the major role of these two systems as targets of ethanol, we wanted to explore additional possible mechanisms underlying changes in GABAergic and glutamatergic responses after chronic ethanol exposure. Therefore, the objective of the present study was to examine GABAergic- and glutamatergic-associated proteins at three days of ethanol withdrawal, when female rats appear to have largely recovered but male rats still display robust signs of withdrawal. Methods: Male and female rats were fed 6% ethanol in a nutritionally complete liquid diet for 14 days according to a pair-fed design; withdrawal was initiated by replacement of the diet with chow. At three days of withdrawal, the cerebral cortex and hippocampus were dissected for use in Western blot analysis. The paired design was maintained throughout all experimental procedures. Results: At three days of ethanol withdrawal, we found region-specific and sex-selective alterations in levels of GAD (glutamic acid decarboxylase, GABA synthetic enzyme), GABA and glutamate transporters, and the synapse-associated proteins HSP70, PSD-95, and synaptophysin. There were also several significant differences in transporter function at this time that varied between males and females. Conclusions: Taken together, these findings show differential adaptations of GABAergic and glutamatergic neurotransmission between female and male rats that are associated with withdrawal recovery. This suggests that selective withdrawal-induced neuroadaptations in regulation of these systems' activities underlie, at least in part, sex differences in withdrawal recovery between male and female rats. [source] Glutamatergic systems in Alzheimer's diseaseINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue S1 2003Paul T. Francis Abstract Glutamate is the major transmitter of the brain and is involved in all aspects of cognitive function since it is the transmitter of cortical and hippocampal pyramidal neurones. Furthermore, glutamate and glutamate receptors are involved in long-term potentiation, a process believed to underlie learning and memory. Histological studies indicate loss of pyramidal neurones and their synapses in Alzheimer's disease (AD), this together with biochemical evidence suggests presynaptic (and postsynaptic) glutamatergic hypoactivity. This represents a ,double blow' as the activity of glutamatergic neurones is heavily influenced by the cholinergic system, which is also dysfunctional in AD. The clinical relevance of these changes is emphasised because glutamatergic and cholinergic dysfunction are strong correlates of cognitive decline in AD. The mechanism by which glutamatergic (and cholinergic) cells die is likely to be a combination of necrosis and apoptosis caused by a range of factors which include tangle formation and the effects of too much and too little glutamatergic neurotransmission. Copyright © 2003 John Wiley & Sons, Ltd. [source] An update on the role of glutamate in the pathophysiology of depressionACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2010N. D. Mitchell Mitchell ND, Baker GB. An update on the role of glutamate in the pathophysiology of depression. Objective:, To review the literature on the involvement of glutamate (Glu), including its interactions with other neurochemical systems, in the pathophysiology of depression. Method:, A MEDLINE search using the terms glutamate, depression and major depressive disorder, was performed. Results:, Alterations in proteins involved in glutamatergic signalling are implicated in variations in behaviour in animal models of depression. Drugs acting at Glu receptors appear to have antidepressant-like effects in these models, and traditional antidepressant pharmacotherapies act on the glutamatergic system. Recent evidence from genetic studies and in vivo spectroscopy also correlate glutamatergic dysfunction with depression. Trials of N -methyl- d -aspartate receptor antagonists in humans have provided mixed results. Conclusion:, A growing body of evidence indicates that the glutamatergic system is involved in the pathophysiology of depression, and may represent a target for intervention. [source] VIQ-PIQ Discrepancies in Partial Epilepsy: On the Relation to Lat- eralities of Focal MRI Lesions, P3 Peaks, and Focal Spikes.EPILEPSIA, Issue 2000Osamu Kanazawa Purpose: A number of previous ncurophysiological studies have indicated that the glutamatergic system is important in the induction of epileptiform activity and the dcvelopment of epileptogenesis. Clutamate transport is the primary mechanism of inactivation of syiiaptically released glutamate. GLAST is classified BS an astrocytic transporter and occurs in high concentrations in the ccrebcllum. The pathophysiologic rolc of GLAST in epilepsy is not known in detail. To investigate the role of thc astroglial glutamatc transporter GLAST in epileptogenesis, we compared amygdalu-kindling and pentylenctetrazolc (PTZ) induced seizures in GLAST-deficient mice (GLAST(-/-)) wild-type mice (GLAST(+/+)), and maternal C57Black6/J mice (C57). Purpose: Subtest IQ such as verbal IQ (VIQ) and performance IQ (PIQ) in WAIS or WISC are thought to represent neuropsychological functions of the left and right hemispheres, respectively. The P300 (P3) event-related potential reflects cognitive processes. We do not ye1 know the brain site of P3 origin or how epileptogenic foci (EF) influ- ence P3 potentials. To examine neuropsychological influence by partial epilepsy (PE), we studied VIQ-PIQ discrepancies in PE in relation to lateralities of focal MRI lesions, P3 peaks, and EF. Methods: Thirteen patients showed VIQ-PIQ discrepancies significant at the p7lt;O.O5 level, represented by a>l2-point spread for the WAIS in adults, and a 15-point spread in the WISC in children. We evoked P3 potentials in the individuals with discrepant IQ differences by asking them to keep a mental count of rare tones, including introduction of oddbail tones. EEGs were recorded by the international 10,20 system and P3 peaks were shown in a topographical view by offline analysis. Patients were divided into normal and abnormal groups according to MRI findings, and were examined for the laterali- ties of the dominant side in subtest IQ (conventionally, we regarded higher VIQ as left hemisphere dominant and higher PIQ as right hemisphere dominant), P3 peaks, and EF. We did not correlate results with lert or right handedness. Results: Five patients (38.5%) were in the normal group and 8 patients (61.5%) were in the abnormal group. Concordance of the lateralities in P3 peaks and dominant side in subtest IQ was shown in 1 patient (20%) in the normal group and 5 patients (62.5%) in the abnormal group. In the normal group, all patients showed contralateral P3 peak shift to EF, and all except I patient showed contralateral P3 peak shift to the dominant side in subtest IQ. The other 3 patients in the abnormal group showed unilateral focal cortical dysplasias (FCD), ipsilateral P3 shift, and contralateral dominant side in subtest IQ to the focal MRI lesions. Conclusion: In our partial epilepsy series with VIQ-PIQ discrepancies, concordance of the lateralities in P3 peaks and dominant side in subtest IQ was shown in < half of the patients. Epileptogenic foci seem to have 3 different grades of influence on P3 peak shift and dominant side in subtest IQ according to the severities of accompanying focal MRI lesions: 1. Without MRI lesions, EF can make P3 peak shift contralaterally, but the dominant side in the subtest IQ shift ipsilaterally; 2. With less severe focal MRI lesions such as hippocampal atrophy etc., EF can make not only P3 peaks but also the dominant side in the subtest IQ shift contralaterally; 3. With severe focal MRI lesions such as FCD, EF can make the dominant side in the subtest IQ shift contralaterally, but the P3 peak may shift ipsilaterally. Epileptogenic foci without MRI lesions seem to control ipsilateral P3 potentials. MRI lesions render a hemisphere unlikely to become dominant, but epileptogenic foci can coexist with apparently normal neuropsychological function. [source] Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarrayEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2002Raffaella Molteni Abstract Studies were performed to determine the effects of acute and chronic voluntary periods of exercise on the expression of hippocampal genes. RNAs from rodents exposed to a running wheel for 3, 7 and 28 days were examined using a microarray with 1176 cDNAs expressed primarily in the brain. The expression of selected genes was quantified by Taqman RT-PCR or RNase protection assay. The largest up-regulation was observed in genes involved with synaptic trafficking (synapsin I, synaptotagmin and syntaxin); signal transduction pathways (Ca2+/calmodulin-dependent protein kinase II, CaM-KII; mitogen-activated/extracellular signal-regulated protein kinase, MAP-K/ERK I and II; protein kinase C, PKC-,) or transcription regulators (cyclic AMP response element binding protein, CREB). Genes associated with the glutamatergic system were up-regulated (N -methyl- d -aspartate receptor, NMDAR-2A and NMDAR-2B and excitatory amino acid carrier 1, EAAC1), while genes related to the gamma-aminobutyric acid (GABA) system were down-regulated (GABAA receptor, glutamate decarboxylase GAD65). Brain-derived neurotrophic factor (BDNF) was the only trophic factor whose gene was consistently up-regulated at all timepoints. These results, together with the fact that most of the genes up-regulated have a recognized interaction with BDNF, suggest a central role for BDNF on the effects of exercise on brain plasticity. The temporal profile of gene expression seems to delineate a mechanism by which specific molecular pathways are activated after exercise performance. For example, the CaM-K signal system seems to be active during acute and chronic periods of exercise, while the MAP-K/ERK system seems more important during long-term exercise. [source] Alcohol Consumption and the Body's Biological ClockALCOHOLISM, Issue 8 2005Rainer Spanagel This review summarizes new findings on the bidirectional interactions between alcohol and the clock genes, underlying the generation of circadian rhythmicity. At the behavioral level, both adult and perinatal ethanol treatments alter the free-running period and light response of the circadian clock in rodents; genetic ethanol preference in alcohol-preferring rat lines is also associated with alterations in circadian pacemaker function. At the neuronal level, it has been shown that ethanol consumption alters the circadian expression patterns of period (per) genes in various brain regions, including the suprachiasmatic nucleus. Notably, circadian functions of ,-endorphin,containing neurons that participate in the control of alcohol reinforcement become disturbed after chronic alcohol intake. In turn, per2 gene activity regulates alcohol intake through its effects on the glutamatergic system through glutamate reuptake mechanisms and thereby may affect a variety of physiological processes that are governed by our internal clock. In summary, a new pathologic chain has been identified that contributes to the negative health consequences of chronic alcohol intake. Thus, chronic alcohol intake alters the expression of per genes, and, as a consequence, a variety of neurochemical and neuroendocrine functions become disturbed. Further steps in this pathologic chain are alterations in physiological and immune functions that are under circadian control, and, as a final consequence, addictive behavior might be triggered or sustained by this cascade. [source] Bipolar disorder: candidate drug targets,MOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 3 2008Carlos A. Zarate Jr Abstract Current pharmacotherapy for bipolar disorder is generally unsatisfactory for a large number of patients. Even with adequate modern bipolar pharmacological therapies, many afflicted individuals continue to have persistent mood episode relapses, residual symptoms, functional impairment, and psychosocial disability. Creating novel therapeutics for bipolar disorder is urgently needed. Promising drug targets and compounds for bipolar disorder worthy of further study include both systems and intracellular pathways and targets. Specifically, the purinergic system, the dynorphin opioid neuropeptide system, the cholinergic system (muscarinic and nicotinic systems), the melatonin and serotonin [5-hydroxytryptamine receptor 2C] system, the glutamatergic system, and the hypothalamic-pituitary adrenal axis have all been implicated. Intracellular pathways and targets worthy of further study include glycogen synthase kinase-3 protein, protein kinase C, and the arachidonic acid cascade. Mt Sinai J Med 75:225,246, 2008. © 2008 Mount Sinai School of Medicine [source] RESEARCH FOCUS ON COMPULSIVE BEHAVIOUR IN ANIMALS: Compulsive alcohol drinking in rodentsADDICTION BIOLOGY, Issue 4 2009Valentina Vengeliene ABSTRACT Upon prolonged alcohol exposure, the behaviour of an individual can gradually switch from controlled to compulsive. Our review is focused on the neurobiological mechanisms that might underlie this transition as well as the factors that are influencing it. Animal studies suggest that temporally increased alcohol consumption during post-abstinence drinking is accompanied by a loss of flexibility of the behaviour and therefore, could serve as a model for compulsive alcohol drinking. However, studies using different alcohol-preferring rat lines in the post-abstinence drinking model suggest that high alcohol consumption does not necessarily lead to the development of compulsive drinking. This indicates the significance of genetic predisposition to compulsive behaviour. Neuroimaging data show that chronic alcohol consumption affects the activity of several brain regions such as the extrapyramidal motor system and several areas of the prefrontal cortex including the orbitofrontal and anterior cingulate cortex. Similar changes in brain activity is seen in patients suffering from obsessive,compulsive disorder at baseline conditions and during provocation of obsessive thoughts and urge to perform compulsive-like rituals. This indicates that dysfunction of these regions may be responsible for the expression of compulsive components of alcohol drinking behaviour. Several brain neurotransmitter systems seem to be responsible for the switch from controlled to compulsive behaviour. In particular, hypofunctioning of monoaminergic systems and hyperfunctioning of glutamatergic systems may play a role in compulsive alcohol drinking. [source] Ethanol Dependence Has Limited Effects on GABA or Glutamate Transporters in Rat BrainALCOHOLISM, Issue 4 2001Leslie L. Devaud Background: Neuroadaptations of GABAergic and glutamatergic systems appear to play an important role in both the acute as well as chronic effects of ethanol. Chronic ethanol intake leads to the development of ethanol tolerance and dependence that is associated with a decrease in GABAergic and an increase in glutamatergic function. The present report assessed the involvement of GABA and glutamate transporters in the chronic ethanol-induced adaptations of these two neuronal systems. Methods: Male and female rats were made ethanol dependent by 2-week administration of ethanol in a liquid diet. Levels of GABA (GAT-1, GAT-3) and glutamate (GLT-1, EAAC-1) transporters were assayed by immunoblotting. Transporter function was assessed by [3H]GABA and [3H]glutamate uptake assays. Results: Ethanol dependence did not alter levels of GABA or glutamate transporters in cerebral cortex compared with pair-fed control values. There were increases in some, but not all, transporter levels in hippocampus and hypothalamus with the development of ethanol dependence. A decreased rate of uptake was observed for GABA in cerebral cortex. There was no change in maximal GABA uptake or in glutamate uptake (Vmax). Conclusions: These results suggest that alterations in GABA and glutamate transporters have only a limited role in neuroadaptations to chronic ethanol intake in rats. However, the observed alterations were region-specific, supporting the complex responses to chronic ethanol exposure and suggesting that neuroadaptations of GABAergic and glutamatergic systems vary across the brain. [source] Postnatal changes of vesicular glutamate transporter (VGluT)1 and VGluT2 immunoreactivities and their colocalization in the mouse forebrainTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 3 2005Kouichi Nakamura Abstract Vesicular glutamate transporter 1 (VGluT1) and VGluT2 accumulate neurotransmitter glutamate into synaptic vesicles at presynaptic terminals, and their antibodies are thus considered to be a good marker for glutamatergic axon terminals. In the present study, we investigated the postnatal development and maturation of glutamatergic neuronal systems by single- and double-immunolabelings for VGluT1 and VGluT2 in mouse forebrain including the telencephalon and diencephalon. VGluT2 immunoreactivity was widely distributed in the forebrain, particularly in the diencephalon, from postnatal day 0 (P0) to adulthood, suggesting relatively early maturation of VGluT2-loaded glutamatergic axons. In contrast, VGluT1 immunoreactivity was intense only in the limbic regions at P0, and drastically increased in the other telencephalic and diencephalic regions during three postnatal weeks. Interestingly, VGluT1 immunoreactivity was frequently colocalized with VGluT2 immunoreactivity at single axon terminal-like profiles in layer IV of the primary somatosensory area from P5 to P10 and in the ventral posteromedial thalamic nucleus from P0 to P14. This was in sharp contrast to the finding that almost no colocalization was found in glomeruli of the olfactory bulb, patchy regions of the caudate-putamen, and the ventral posterolateral thalamic nucleus, where moderate to intense immunoreactivities for VGluT1 and VGluT2 were intermingled with each other in neuropil during postnatal development. The present results indicate that VGluT2-loaded glutamatergic axons maturate earlier than VGluT1-laden axons in the mouse telencephalic and diencephalic regions, and suggest that VGluT1 plays a transient developmental role in some glutamatergic systems that mainly use VGluT2 in the adulthood. J. Comp. Neurol. 492:263,288, 2005. © 2005 Wiley-Liss, Inc. [source] | |||||||||||||