The Neurotoxicity Induced by Ethanol Withdrawal in Mature Organotypic Hippocampal Slices Might Involve Cross‐Talk Between Metabotropic Glutamate Type 5 Receptors and <i>N</i>‐Methyl‐d‐Aspartate Receptors

Harris, Barton R.; Gibson, D. Alex; Prendergast, Mark A.; Blanchard, John; Holley, Robert C.; Hart, Stewart R.; Scotland, Rebecca L.; Foster, Thomas C.; Pedigo, Norman W.; Littleton, John M.

doi:10.1097/01.alc.0000093601.33119.e3

Cited by 86 publications

(67 citation statements)

References 56 publications

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“…Also, in the CA1 region of ethanol pre-treated organotypic hippocampal slices, where neurotoxicity was observed after a 24-hr withdrawal, acamprosate, as well as SIB-1893, MK-801, and staurosporine were all neuroprotective. In this ethanol pre-treated slice culture preparations the polypeptide levels of mGluR5 receptors were found to be increased [77], similarly as the NR1 and NR2B subunits of NMDARs in other neuronal cultures after long-term ethanol exposure [150,176]. Considering these observations, acamprosate may act on the mGluR5 receptors reducing its positive feedback control over the NMDARs [217].…”

Section: Acamprosatementioning

confidence: 61%

“…Besides several other factors (e.g. functional deficits of GABA receptors and increased VGCC function [77,212]), the NMDARs are major contributors to the increased glutamate release during alcohol withdrawal since in the brain of ethanol-dependent rats, the extracellular concentration of glutamate shows a transient, NMDAR mediated increase after cessation of ethanol intake and these changes are time-locked to the behavioural signs of ethanol withdrawal [44,53,183]. This enhanced glutamate release may contribute to the further shift towards the excitatory dominance in the CNS after ethanol withdrawal [184].…”

Section: Consequences Of Increased Nmdar Functionmentioning

confidence: 99%

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Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

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Section: Acamprosatementioning

confidence: 61%

Section: Consequences Of Increased Nmdar Functionmentioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

View full text Add to dashboard Cite

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“…From the mechanistic point of view, acamprosate is reported to act as a functional NMDA receptor antagonistFpartially through an interplay with mGluR5 receptors (Harris et al, 2002(Harris et al, , 2003Fmodulating activity of dopaminergic neurons within the mesolimbic reward system (Olive et al, 2002;Cano-Cebrian et al, 2003). Since augmented dopaminergic activity is thought to underlie drug-seeking responses (Spanagel and Weiss, 1999;Liu and Weiss, 2002), in reinstatement experiments acamprosate might attenuate ethanol-paired cue effects through an inhibition of glutamatergic activity and a subsequent decrease of dopaminergic function.…”

Section: Discussionmentioning

confidence: 99%

“…Acamprosate can modulate hyper-glutamatergic activity by a variety of actions. Specifically, it regulates NMDA receptor subunit composition Rammes et al, 2001), binds to a specific spermidine-sensitive site modulating the NMDA receptor in a complex way (AlQatari et al, 1998;Naassila et al, 1998), blocks voltagedependent Ca 2 þ -channels (Littleton, 1995;Allgaier et al, 2000), or as recently hypothesized, interacts with group I metabotropic glutamate receptors subtype 5 (mGluR5) (Harris et al, 2002(Harris et al, , 2003.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Acamprosate and Neramexane on Cue-Induced Reinstatement of Ethanol-Seeking Behavior in Rat

Bachteler

Economidou

Danysz

et al. 2005

Neuropsychopharmacol

108

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This study examines, for the first time, the effects of acamprosate and the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist neramexane on ethanol-seeking induced by alcohol-related environmental stimuli in an animal model of relapse. Wistar rats were trained to operantly self-administer ethanol (10% w/v) or water on a fixed-ratio 1 schedule in a 30-min daily session. Ethanol availability was signaled by an olfactory discriminative stimulus of orange extract (S þ ). In addition, each lever press was accompanied by a 5-s illumination of the operant chamber's house light (CS þ ). Water availability was signaled by anise odor (S À ) and 5-s white noise stimulus (CS À ). After completion of the conditioning phase, indicated by stable levels of responding, operant behaviors were extinguished. Prior to reinstatement tests, animals were divided into groups according to either treatment with acamprosate (100, 200 mg/kg given twice), neramexane (1.0, 2.0, 4.0 mg/kg), or vehicle. In vehicle-treated rats, re-exposure to the S þ /CS þ in the absence of further ethanol availability elicited strong recovery of responding. No effect was observed following presentation of water-paired cues (S À /CS À ). Acamprosate dose-dependently attenuated recovery of responding elicited by ethanol-paired cues (S þ /CS þ ), whereas responding under S À /CS À was not modified by drug administration. Treatment with 1.0 and 2.0 mg/kg of neramexane did not significantly modify responding under both S þ /CS þ and S À /CS À conditions. However, a slight reduction of cue-induced reinstatement of alcohol seeking was observed. At the dose of 4.0 mg/kg, neramexane elicited a marked inhibition of responding following presentation of both ethanol-and water-paired cues. In conclusion, acamprosate significantly and selectively reduced alcohol-seeking elicited by environmental stimuli predictive of alcohol availability. Treatment with neramexane that shares part of the pharmacological effects of acamprosate on NMDA receptors, however, resulted in a nonselective reduction of lever responding.

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“…Thus, activation of different receptor types may either attenuate or exacerbate intracellular events caused by the simultaneous activation of other types of GluRs on the same cell. Such cross-talk has been demonstrated for functional interactions in neuronal cells between different types of iGluRs (Carpenter 2002) and also in both directions between mGluRs and NMDA-activated iGluRs (Boldyrev 2000;Krieger et al 2000;Hermans and Challiss 2001;Harris et al 2003). There is strong evidence that the interaction between activated iGluRs and mGluRs is involved in neuroplasticity in vivo (Jeffery and Hayman 2004).…”

mentioning

confidence: 92%

Emerging evidence for a similar role of glutamate receptors in the nervous and immune systems

Boldyrev

Carpenter

Johnson

2005

Journal of Neurochemistry

112

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The role of glutamate receptors in synaptic transmission and excitotoxicity in the nervous system is well established. Recent evidence has emerged that glutamatergic mechanisms also exist in a wide variety of non-neuronal cells. In the case of thymocytes and lymphocytes, several types of glutamate receptor are expressed which can induce functional changes. This review focuses on the cellular function of NMDA-activated ionotropic and groups I and III metabotropic glutamate receptors in lymphocytes. Levels of exogenous and endogenous circulatory agonists and antagonists for lymphocyte glutamate receptors, notably homocysteine metabolites, are markedly increased in certain disease states and may be involved in disorders of the immune system. In addition to glutamate and aspartate, these compounds are active at glutamate receptors and increase the excitotoxic effects of glutamate in both neurons and lymphocytes. Increased levels of compounds acting at glutamate receptors may be risk factors for organ damage, for example in both heart and kidney disease. We conclude that glutamate is involved in signaling in immunocompetent cells and that the expression of both ionotropic and metabotropic glutamate receptors may have regulatory functions in immunocompetent cells, as well as in the nervous system. In addition, glutamate may serve as a signaling agent between the immune and nervous systems. Abbreviations used: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CDCF, carboxy-dichlorofluorescein; CSA, cysteine sulfinic acid; GluR, glutamate receptor; HC, homocysteine; HCA, homocysteic acid; iGluR, ionotropic glutamate receptor; L-AP4, L-2-amino-4-phosphonobutyric acid; mGluR, metabotropic glutamate receptor; PI, propidium iodide; ROS, reactive oxygen species.

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The Neurotoxicity Induced by Ethanol Withdrawal in Mature Organotypic Hippocampal Slices Might Involve Cross‐Talk Between Metabotropic Glutamate Type 5 Receptors and N‐Methyl‐d‐Aspartate Receptors

Abstract: From this model of long-term ethanol exposure and withdrawal, the functional interplay between mGluR5s and NMDARs might represent a novel target for the prevention of neurotoxicity associated with ethanol withdrawal.

Cited by 86 publications

References 56 publications

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

The Effects of Acamprosate and Neramexane on Cue-Induced Reinstatement of Ethanol-Seeking Behavior in Rat

Emerging evidence for a similar role of glutamate receptors in the nervous and immune systems

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