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  1. Article: Methamphetamine exposure antagonizes N-methyl-D-aspartate receptor-mediated neurotoxicity in organotypic hippocampal slice cultures.

    Smith, Katherine J / Self, Rachel L / Butler, Tracy R / Mullins, Michael M / Ghayoumi, Layla / Holley, Robert C / Littleton, John M / Prendergast, Mark A

    Brain research

    2007  Volume 1157, Page(s) 74–80

    Abstract: Glutamatergic systems have been increasingly recognized as mediators of methamphetamine's (METH) pharmacological effects though little is known about the means by which METH interacts with glutamate receptors. The present studies examined effects of METH ...

    Abstract Glutamatergic systems have been increasingly recognized as mediators of methamphetamine's (METH) pharmacological effects though little is known about the means by which METH interacts with glutamate receptors. The present studies examined effects of METH (0.1-100 microM) on [3H]MK-801 binding to membranes prepared from adult rat cortex, hippocampus and cerebellum, as well as the neurotoxicity produced by 24-h exposure to N-methyl-D-aspartate (5-10 microM; NMDA) employing organotypic hippocampal slice cultures of neonatal rat. Co-incubation of [3H]MK-801 with METH (0.1-100 microM) did not reduce dextromethorphan (1 mM)-displaceable ligand binding. Exposure of slice cultures to NMDA for 24-h produced increases in uptake of the non-vital fluorescent marker propidium iodide (PI) of 150-500% above control levels, most notably, in the CA1 region pyramidal cell layer. Co-exposure to METH (>1.0 microM) with NMDA (5 microM) reduced PI uptake by approximately 50% in each subregion, though the CA1 pyramidal cell layer was markedly more sensitive to the protective effects of METH exposure. In contrast, METH exposure did not reduce PI uptake stimulated by 24-h exposure to 10 microM NMDA. Co-exposure to the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (20 microM) prevented toxicity produced by exposure to 5 or 10 microM NMDA. These findings indicate that the pharmacological effects of short-term METH exposure involve inhibition of NMDA receptor-mediated neuronal signaling, not reflective of direct channel inhibition at an MK-801-sensitive site.
    MeSH term(s) 2-Amino-5-phosphonovalerate/pharmacology ; Animals ; Animals, Newborn ; Binding, Competitive/drug effects ; Binding, Competitive/physiology ; Central Nervous System Stimulants/toxicity ; Dizocilpine Maleate/metabolism ; Dose-Response Relationship, Drug ; Drug Antagonism ; Excitatory Amino Acid Agonists/pharmacology ; Excitatory Amino Acid Antagonists/metabolism ; Female ; Glutamic Acid/metabolism ; Hippocampus/drug effects ; Hippocampus/metabolism ; Hippocampus/physiopathology ; Male ; Methamphetamine/pharmacology ; N-Methylaspartate/pharmacology ; Neurons/drug effects ; Neurons/metabolism ; Neurotoxins/toxicity ; Organ Culture Techniques ; Pyramidal Cells/drug effects ; Pyramidal Cells/metabolism ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism ; Synaptic Transmission/drug effects ; Synaptic Transmission/physiology
    Chemical Substances Central Nervous System Stimulants ; Excitatory Amino Acid Agonists ; Excitatory Amino Acid Antagonists ; Neurotoxins ; Receptors, N-Methyl-D-Aspartate ; Glutamic Acid (3KX376GY7L) ; Methamphetamine (44RAL3456C) ; N-Methylaspartate (6384-92-5) ; Dizocilpine Maleate (6LR8C1B66Q) ; 2-Amino-5-phosphonovalerate (76726-92-6)
    Language English
    Publishing date 2007-07-09
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2007.04.056
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  2. Article: Potential value of changes in cell markers in organotypic hippocampal cultures associated with chronic EtOH exposure and withdrawal: comparison with NMDA-induced changes.

    Wilkins, Lincoln H / Prendergast, Mark A / Blanchard, John / Holley, Robert C / Chambers, Elton R / Littleton, John M

    Alcoholism, clinical and experimental research

    2006  Volume 30, Issue 10, Page(s) 1768–1780

    Abstract: Background: Previous studies have shown that withdrawal from ethanol (EtOH) exposure induces neuronal damage, as indicated by propidium iodide (PI) uptake, in organotypic hippocampal slice cultures. This is prevented by MK801, suggesting that damage is " ...

    Abstract Background: Previous studies have shown that withdrawal from ethanol (EtOH) exposure induces neuronal damage, as indicated by propidium iodide (PI) uptake, in organotypic hippocampal slice cultures. This is prevented by MK801, suggesting that damage is "excitotoxic," resulting from activation of N-methyl-d-aspartate (NMDA) receptors by endogenous glutamate. To avoid reliance on a single indicator, and to enable assessment of recovery from the EtOH withdrawal (EWD) insult, we assessed changes in cell markers for neurons and glia, as well as cell division, following either EWD or NMDA challenge (as a positive control).
    Methods: Organotypic cultures from postnatal day (PND) 8 rats were cultured for 5 days before exposure to EtOH (mean concentration approximately 65 mM) for 10 days before EWD. Cultures of the same "days in vitro" age (DIV16) were exposed to NMDA (200 microM) for 1 hour. Neuronal injury was visualized using PI and indices of neurons, glia, or cell division were measured at intervals up to 10 days following the neurotoxic insults. Each time point and measurement used separate slice cultures, and these were treated as separate experiments with paired controls. Regional neuronal content was assessed by neuronal nuclear protein (NeuN) and calbindin D28k (Calb), glial content by glial fibrillary acidic protein (GFAP), and cell division by bromodeoxyuridine (BrdU) incorporation, all measured immunohistochemically.
    Results: Chronic exposure to EtOH was associated with a dramatic reduction in BrdU incorporation in all regions of cultures. Propidium iodide fluorescence in the CA1 region was elevated significantly after EWD and more so after NMDA challenge. Reduced immunoreactivity (IR) of NeuN and Calb suggested that loss of neurons resulted from the EWD insult. Bromodeoxyuridine incorporation was initially depressed even further by EWD, but had returned to control levels after 3 days. In contrast, following NMDA insult, BrdU incorporation was significantly and persistently elevated above control levels after 3 days. Glial fibrillary acidic protein was reduced immediately after both EWD and NMDA challenge. Several days after EWD, expression of neuronal and glial markers, although variable, had generally returned to control levels. In contrast, NeuN IR remained significantly reduced after NMDA challenge.
    Conclusions: In general, the use of additional markers supports data obtained with PI uptake alone and suggests that neurons (and glia) are lost from the culture following EWD or NMDA challenge. These cell markers recover several days after EWD, but it is unclear whether functional recovery accompanies these changes. If the dramatic effect of EtOH exposure and EWD on BrdU incorporation reflects reduced neuro- and gliogenesis, it is likely that this adversely affects long-term recovery from EWD. Finally, some markers showed significant and consistent changes after EWD, whereas others did not. This information may facilitate the use of this model in evaluation of potential medications that protect against and/or promote recovery from neurotoxicity.
    MeSH term(s) Animals ; Antigens, Nuclear/metabolism ; Biomarkers/metabolism ; Calbindin 1 ; Calbindins ; Cell Division/drug effects ; Central Nervous System Depressants/pharmacology ; Disease Models, Animal ; Ethanol/pharmacology ; Excitatory Amino Acid Agonists/pharmacology ; Female ; Glial Fibrillary Acidic Protein/metabolism ; Hippocampus/cytology ; Hippocampus/drug effects ; Hippocampus/metabolism ; Male ; N-Methylaspartate/pharmacology ; Nerve Tissue Proteins/metabolism ; Neurons/cytology ; Neurons/metabolism ; Organ Culture Techniques ; Propidium/pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; S100 Calcium Binding Protein G/metabolism ; Substance Withdrawal Syndrome/metabolism
    Chemical Substances Antigens, Nuclear ; Biomarkers ; Calb1 protein, rat ; Calbindin 1 ; Calbindins ; Central Nervous System Depressants ; Excitatory Amino Acid Agonists ; Glial Fibrillary Acidic Protein ; Nerve Tissue Proteins ; S100 Calcium Binding Protein G ; Propidium (36015-30-2) ; Ethanol (3K9958V90M) ; N-Methylaspartate (6384-92-5)
    Language English
    Publishing date 2006-10
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 428999-7
    ISSN 1530-0277 ; 0145-6008
    ISSN (online) 1530-0277
    ISSN 0145-6008
    DOI 10.1111/j.1530-0277.2006.00210.x
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  3. Article: Opposing effects of ethanol and nicotine on hippocampal calbindin-D28k expression.

    Mulholland, Patrick J / Harris, Barton R / Wilkins, Lincoln H / Self, Rachel L / Blanchard, John A / Holley, Robert C / Littleton, John M / Prendergast, Mark A

    Alcohol (Fayetteville, N.Y.)

    2003  Volume 31, Issue 1-2, Page(s) 1–10

    Abstract: Long-term ethanol exposure produces multiple neuroadaptations that likely contribute to dysregulation of Ca(2+) balance and neurotoxicity during ethanol withdrawal. Conversely, nicotine exposure may reduce the neurotoxic consequences of Ca(2+) ... ...

    Abstract Long-term ethanol exposure produces multiple neuroadaptations that likely contribute to dysregulation of Ca(2+) balance and neurotoxicity during ethanol withdrawal. Conversely, nicotine exposure may reduce the neurotoxic consequences of Ca(2+) dysregulation, putatively through up-regulation of the Ca(2+)-buffering protein calbindin-D(28k). The current studies were designed to examine the extent to which 10-day ethanol exposure and withdrawal altered calbindin-D(28k) expression in rat hippocampus. Further, in these studies, we examined the ability of nicotine, through action at alpha(7)(*)-bearing nicotinic acetylcholine receptors (nAChRs), to antagonize the effects of ethanol exposure on calbindin-D(28k) expression. Organotypic cultures of rat hippocampus were exposed to ethanol (50-100 mM) for 10 days. Additional cultures were exposed to 500 nM (-)-nicotine with or without the addition of 50 mM ethanol, 100 nM methyllycaconitine (an alpha(7)*-bearing nAChR antagonist), or both. Prolonged exposure to ethanol (>/=50 mM) produced significant reductions of calbindin-D(28k) immunolabeling in all regions of the hippocampal formation, even at nontoxic concentrations of ethanol. Calbindin-D(28k) expression levels returned to near-control levels after 72 h of withdrawal from 10-day ethanol exposure. Extended (-)-nicotine exposure produced significant elevations in calbindin-D(28k) expression levels that were prevented by methyllycaconitine co-exposure. Co-exposure of cultures to (-)-nicotine with ethanol resulted in an attenuation of ethanol-induced reductions in calbindin-D(28k) expression levels. These findings support the suggestion that long-term ethanol exposure reduces the neuronal capacity to buffer accumulated Ca(2+) in a reversible manner, an effect that likely contributes to withdrawal-induced neurotoxicity. Further, long-term exposure to (-)-nicotine enhances calbindin-D(28k) expression in an alpha(7)* nAChR-dependent manner and antagonizes the effects of ethanol on calbindin-D(28k) expression.
    MeSH term(s) Animals ; Calbindin 1 ; Calbindins ; Dose-Response Relationship, Drug ; Ethanol/pharmacology ; Female ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/physiology ; Hippocampus/chemistry ; Hippocampus/drug effects ; Hippocampus/metabolism ; Male ; Nicotine/pharmacology ; Rats ; Rats, Sprague-Dawley ; S100 Calcium Binding Protein G/analysis ; S100 Calcium Binding Protein G/biosynthesis ; Substance Withdrawal Syndrome/metabolism
    Chemical Substances Calb1 protein, rat ; Calbindin 1 ; Calbindins ; S100 Calcium Binding Protein G ; Ethanol (3K9958V90M) ; Nicotine (6M3C89ZY6R)
    Language English
    Publishing date 2003-08-15
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 605912-0
    ISSN 0741-8329
    ISSN 0741-8329
    DOI 10.1016/j.alcohol.2003.09.001
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  4. Article: Polyamines contribute to ethanol withdrawal-induced neurotoxicity in rat hippocampal slice cultures through interactions with the NMDA receptor.

    Gibson, D Alex / Harris, Barton R / Prendergast, Mark A / Hart, Stewart R / Blanchard, John A / Holley, Robert C / Pedigo, Norman W / Littleton, John M

    Alcoholism, clinical and experimental research

    2003  Volume 27, Issue 7, Page(s) 1099–1106

    Abstract: Background: Several reports demonstrate that withdrawal from long-term ethanol exposure is associated with significant central nervous system neurotoxicity, produced at least in part by increased activity of N-methyl-d-aspartate receptors (NMDARs). ... ...

    Abstract Background: Several reports demonstrate that withdrawal from long-term ethanol exposure is associated with significant central nervous system neurotoxicity, produced at least in part by increased activity of N-methyl-d-aspartate receptors (NMDARs). Recent evidence suggests that elevations in the synthesis and release of the polyamines spermidine and spermine, which are known modulators of NMDARs, contribute to the increased activity of the receptor during ethanol withdrawal. Therefore, the goal of this investigation was to examine what role, if any, spermidine and spermine have in the generation of ethanol withdrawal-induced neurotoxicity.
    Methods: Neurotoxicity (measured as fluorescence of the cell death indicator propidium iodide, PI), glutamate release (measured by high-performance liquid chromatography analysis), and polyamine concentrations (by high-performance liquid chromatography) were measured in rat hippocampal slice cultures undergoing withdrawal from chronic (10 day) ethanol exposure (100 mM). In addition, the effects of the polyamine synthesis inhibitor di-fluoro-methyl-ornithine (DFMO, 0.1-100 nM) and NMDAR polyamine-site antagonists ifenprodil, arcaine, and agmatine (1 nM-100 microM) on ethanol withdrawal- and NMDA-induced neurotoxicity were measured.
    Results: Ethanol withdrawal significantly increased glutamate release (peaking at 18 hr with a 53% increase), increased concentrations of putrescine and spermidine (136% and 139% increases, respectively, at 18 hr), and produced significant cytotoxicity in the CA1 hippocampal region (56% increase in PI staining relative to controls) of the cultures. The cell death produced by ethanol withdrawal was significantly inhibited by ifenprodil (IC(50) = 14.9 nM), arcaine (IC(50) = 37.9 nM), agmatine (IC(50) = 41.5 nM), and DFMO (IC(50) = 0.6 nM). NMDA (5 microM) significantly increased PI staining in the CA1 region of the hippocampal cultures (365% relative to controls), but ifenprodil, arcaine, agmatine, and DFMO all failed to significantly affect this type of toxicity.
    Conclusions: These data implicate a role for polyamines in ethanol withdrawal-induced neurotoxicity and suggest that inhibiting the actions of polyamines on NMDARs may be neuroprotective under these conditions.
    MeSH term(s) Animals ; Biogenic Polyamines/metabolism ; Dose-Response Relationship, Drug ; Ethanol/toxicity ; Excitatory Amino Acid Antagonists/pharmacology ; Female ; Hippocampus/drug effects ; Hippocampus/metabolism ; Male ; Organ Culture Techniques ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate/metabolism ; Substance Withdrawal Syndrome/metabolism
    Chemical Substances Biogenic Polyamines ; Excitatory Amino Acid Antagonists ; Receptors, N-Methyl-D-Aspartate ; Ethanol (3K9958V90M)
    Language English
    Publishing date 2003-07
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 428999-7
    ISSN 1530-0277 ; 0145-6008
    ISSN (online) 1530-0277
    ISSN 0145-6008
    DOI 10.1097/01.ALC.0000075824.10502.DD
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  5. Article: Acamprosate has no effect on NMDA-induced toxicity but reduces toxicity induced by spermidine or by changing the medium in organotypic hippocampal slice cultures from rat.

    Mayer, Sveta / Harris, Barton / Gibson, D Alex / Blanchard, John / Prendergast, Mark A / Holley, Robert C / Littleton, John

    Alcoholism, clinical and experimental research

    2002  Volume 26, Issue 5, Page(s) 655–662

    Abstract: Background: It has been suggested that the antirelapse drug acamprosate can inhibit or potentiate glutamate/NMDA receptor-mediated responses via a polyamine site. Additionally, subchronic exposure to acamprosate increases expression of some NMDA ... ...

    Abstract Background: It has been suggested that the antirelapse drug acamprosate can inhibit or potentiate glutamate/NMDA receptor-mediated responses via a polyamine site. Additionally, subchronic exposure to acamprosate increases expression of some NMDA receptor subunits. These effects on NMDA receptors imply that the drug may have neurotoxic or neuroprotective actions under different conditions, and these studies were undertaken to evaluate this possibility in hippocampal neuronal cultures.
    Methods: Organotypic hippocampal cultures from 8-day-old neonatal rats were maintained in medium for 28 days. The effects of acamprosate (100 microM) alone or on neurotoxic challenges induced by either 50 microM NMDA or 100 microM spermidine were studied. Neurotoxicity was assessed by uptake of propidium iodide 24 hr after challenge. Calcium entry was measured by uptake of 45Ca2+ into the culture during the challenge.
    Results: Acamprosate produced no neurotoxicity in these cultures after acute or subchronic exposure. In contrast, the presence of acamprosate significantly reduced "basal" propidium iodide uptake caused by the medium change procedure; similar effects were obtained with dizocilpine (MK-801; 30 microM) and, to a lesser extent, with ifenprodil (50 microM). Acamprosate did not significantly potentiate or inhibit NMDA-induced neurotoxicity, but the presence of acamprosate significantly reduced spermidine-induced neurotoxicity.
    Conclusion: No evidence was obtained that the putative agonist or coagonist effects of acamprosate on the NMDA receptor are able to cause neurotoxicity. Similarly, no evidence for inhibitory effects of acamprosate on NMDA-induced toxicity was observed under any of these conditions. However, acamprosate significantly inhibited the toxicity associated with changing medium and the toxicity induced by spermidine in these hippocampal cultures. The mechanism is unknown but is compatible with previously reported inhibition of polyamine-mediated effects.
    MeSH term(s) Animals ; Animals, Newborn ; Culture Media/pharmacology ; Female ; Hippocampus/drug effects ; Hippocampus/metabolism ; Male ; N-Methylaspartate/toxicity ; Organ Culture Techniques/statistics & numerical data ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism ; Spermidine/antagonists & inhibitors ; Spermidine/toxicity ; Taurine/analogs & derivatives ; Taurine/pharmacology
    Chemical Substances Culture Media ; Receptors, N-Methyl-D-Aspartate ; Taurine (1EQV5MLY3D) ; N-Methylaspartate (6384-92-5) ; acamprosate (N4K14YGM3J) ; Spermidine (U87FK77H25)
    Language English
    Publishing date 2002-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 428999-7
    ISSN 1530-0277 ; 0145-6008
    ISSN (online) 1530-0277
    ISSN 0145-6008
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  6. Article: Acamprosate, MK-801, and ifenprodil inhibit neurotoxicity and calcium entry induced by ethanol withdrawal in organotypic slice cultures from neonatal rat hippocampus.

    Mayer, Sveta / Harris, Barton R / Gibson, D Alex / Blanchard, John A / Prendergast, Mark A / Holley, Robert C / Littleton, John

    Alcoholism, clinical and experimental research

    2002  Volume 26, Issue 10, Page(s) 1468–1478

    Abstract: Background: The antirelapse drug acamprosate has previously been reported to inhibit activating effects of polyamines on -methyl-D-aspartic acid receptor (NMDAR) function. Because increased synthesis of polyamines has been suggested as a mechanism for ... ...

    Abstract Background: The antirelapse drug acamprosate has previously been reported to inhibit activating effects of polyamines on -methyl-D-aspartic acid receptor (NMDAR) function. Because increased synthesis of polyamines has been suggested as a mechanism for potentiation of NMDAR function during ethanol withdrawal, we evaluated the effects of acamprosate, MK-801, and ifenprodil in a cell culture model of ethanol withdrawal-induced neurotoxicity.
    Methods: Organotypic hippocampal cultures from 8-day-old neonatal rats were maintained in vitro for 23 days before experimental use. The ethanol withdrawal model consisted of exposing cultures to ethanol (70-100 mM) for 4 days before being "withdrawn" into Calcium-Locke's buffer for 1 hr and then into minimal medium for 23 hr. Uptake of (45)CaCl(2) and propidium iodide by damaged cells was assessed 1 hr and 24 hr after the start of ethanol withdrawal, respectively. Additional studies examined effects of exposure to NMDA (50 microM) or spermidine (100 microM) on withdrawal-induced hippocampal damage. Last, these studies examined the ability of the sodium salt of acamprosate (Na-acamprosate, 200 microM), ifenprodil (50 microM), or MK-801 (30 microM) to inhibit neurotoxicity and (45)Ca(2+) entry produced by these insults.
    Results: Ethanol withdrawal was associated with significantly greater toxicity and (45)Ca(2+) entry, relative to controls. Exposure to spermidine and NMDA during ethanol withdrawal further increased neurotoxicity and (45)Ca(2+) entry. Acamprosate, ifenprodil, and MK-801 almost completely prevented ethanol withdrawal-induced toxicity and (45)Ca(2+) entry. Acamprosate also reduced spermidine-induced neurotoxicity during ethanol withdrawal but was ineffective against NMDA-induced toxicity or (45)Ca(2+) entry at this time.
    Conclusions: The results support the contention that acamprosate, like ifenprodil, interacts with polyamines and that these compounds may be effective in reducing consequences of ethanol withdrawal. NMDAR activation is also strongly implicated in ethanol withdrawal neurotoxicity, but whether acamprosate causes any of these effects in this preparation directly via the NMDAR remains uncertain.
    MeSH term(s) Animals ; Animals, Newborn ; Calcium Signaling/drug effects ; Calcium Signaling/physiology ; Dizocilpine Maleate/pharmacology ; Dizocilpine Maleate/therapeutic use ; Ethanol/toxicity ; Female ; Hippocampus/drug effects ; Hippocampus/metabolism ; Hippocampus/pathology ; Male ; Organ Culture Techniques ; Piperidines/pharmacology ; Piperidines/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Substance Withdrawal Syndrome/drug therapy ; Substance Withdrawal Syndrome/metabolism ; Substance Withdrawal Syndrome/pathology ; Taurine/analogs & derivatives ; Taurine/pharmacology ; Taurine/therapeutic use
    Chemical Substances Piperidines ; Taurine (1EQV5MLY3D) ; Ethanol (3K9958V90M) ; Dizocilpine Maleate (6LR8C1B66Q) ; acamprosate (N4K14YGM3J) ; ifenprodil (R8OE3P6O5S)
    Language English
    Publishing date 2002-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 428999-7
    ISSN 1530-0277 ; 0145-6008
    ISSN (online) 1530-0277
    ISSN 0145-6008
    DOI 10.1097/01.ALC.0000033261.14548.D2
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  7. Article: 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.

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

    Alcoholism, clinical and experimental research

    2003  Volume 27, Issue 11, Page(s) 1724–1735

    Abstract: Background: We recently reported that the sodium salt of acamprosate (Na-acamprosate) demonstrates the characteristics of an antagonist at metabotropic glutamate type 5 receptors (mGluR5s) rather than at N-methyl-d-aspartate receptors (NMDARs). Because ... ...

    Abstract Background: We recently reported that the sodium salt of acamprosate (Na-acamprosate) demonstrates the characteristics of an antagonist at metabotropic glutamate type 5 receptors (mGluR5s) rather than at N-methyl-d-aspartate receptors (NMDARs). Because mGluR5s are able to enhance the function of NMDARs, this interplay may be involved in the dysregulation of glutamatergic transmission during ethanol withdrawal. The following studies use organotypic hippocampal slice cultures at a mature age to investigate the potential for this interplay in the neurotoxicity associated with withdrawal from long-term ethanol exposure.
    Methods: At 25 days in vitro, organotypic hippocampal slice cultures prepared from male and female 8-day-old rats were exposed to an initial concentration of 100 mM ethanol for 10 days before undergoing a 24-hr period of withdrawal. The effects of Na-acamprosate; 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at mGluR5s; 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, a noncompetitive antagonist at mGluR1s; dizocilpine (MK-801), a noncompetitive NMDAR antagonist; and staurosporine on the neurotoxicity induced by ethanol withdrawal were assessed by determining differences in propidium iodide uptake. Polypeptide levels of mGluR5s and the NR1 and NR2B subunits of NMDARs were also determined via Western blot analyses after 10 days of ethanol exposure.
    Results: Significant neurotoxicity was always evident in the CA1 hippocampal region after a 24-hr withdrawal period. This spontaneous neurotoxicity resulted from intrinsic changes induced by the long-term presence of ethanol. Na-acamprosate (200-1000 microM), SIB-1893 (200-500 microM), MK-801 (20 microM), and staurosporine (200 nM) were all neuroprotective. The polypeptide levels of mGluR5s and NR1 and NR2B subunits of NMDARs were all increased after ethanol exposure; however, the increase in mGluR5s did not achieve statistical significance.
    Conclusions: 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.
    MeSH term(s) Animals ; Dizocilpine Maleate/pharmacology ; Ethanol/toxicity ; Female ; Hippocampus/drug effects ; Hippocampus/metabolism ; Male ; N-Methylaspartate/pharmacology ; Organ Culture Techniques ; Rats ; Rats, Sprague-Dawley ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate/agonists ; Receptors, Metabotropic Glutamate/antagonists & inhibitors ; Receptors, Metabotropic Glutamate/metabolism ; Receptors, N-Methyl-D-Aspartate/agonists ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate/metabolism ; Substance Withdrawal Syndrome/metabolism
    Chemical Substances Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate ; Receptors, N-Methyl-D-Aspartate ; Ethanol (3K9958V90M) ; N-Methylaspartate (6384-92-5) ; Dizocilpine Maleate (6LR8C1B66Q)
    Language English
    Publishing date 2003-11
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 428999-7
    ISSN 1530-0277 ; 0145-6008
    ISSN (online) 1530-0277
    ISSN 0145-6008
    DOI 10.1097/01.ALC.0000093601.33119.E3
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  8. Article: Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors.

    Harris, Barton R / Prendergast, Mark A / Gibson, D Alex / Rogers, D Trent / Blanchard, John A / Holley, Robert C / Fu, May C / Hart, Stewart R / Pedigo, Norman W / Littleton, John M

    Alcoholism, clinical and experimental research

    2002  Volume 26, Issue 12, Page(s) 1779–1793

    Abstract: Background: Several reported effects of acamprosate within the glutamatergic system could result from interactions with metabotropic glutamate receptors (mGluRs). The following experiments were performed to determine whether acamprosate could compete ... ...

    Abstract Background: Several reported effects of acamprosate within the glutamatergic system could result from interactions with metabotropic glutamate receptors (mGluRs). The following experiments were performed to determine whether acamprosate could compete with trnas-ACPD (+/--1-aminocyclopentane-trans-1,3-dicarboxylic acid, an equimolecular mixture of 1S, 3R and 1R, 3S-ACPD and an agonist at both group I and group II mGluRs) sensitive binding sites and protect against trans-ACPD-induced neurotoxicity in organotypic hippocampal slice cultures.
    Methods: A P2 membrane preparation of cortices, cerebellums, and hippocampi of adult, male Sprague Dawley rats was used to determine the abilities of N-methyl-D-aspartic acid (NMDA) and trans-ACPD to displace [3H]glutamate in both the absence and the presence of the sodium salt of acamprosate (sodium mono N-acetyl homotaurine or Na-acamprosate). A comparison of the effects of 100 microM guanosine 5'-triphosphate on unlabeled glutamate, trans-ACPD, and Na-acamprosate was performed in the same paradigm. For the neurotoxicity studies, organotypic hippocampal slice cultures from male and female 8-day-old neonatal rats were exposed to either 500 microM -ACPD or 50 microM NMDA for 24 hr in normal culture medium containing serum on day 20 in vitro. The effects of Na-acamprosate and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at metabotropic type 5 receptors (mGluR5s), were assessed by determining differences in propidium iodide uptake as compared with neurotoxic challenges alone.
    Results: Na-acamprosate displaced 31% of [3H]glutamate but did not compete with NMDA for [3H]glutamate binding sites. Na-acamprosate displayed total competition with trans-ACPD. The presence of 100 microM guanosine 5'-triphosphate differentially altered the displacing capabilities of the two mGluR agonists, unlabeled glutamate and trans-ACPD, as compared with Na-acamprosate. Na-acamprosate (200-1000 microM) and SIB-1893 (20-500 microM) both were neuroprotective against trans-ACPD induced neurotoxicity that likely results from mGluR potentiation of NMDARs. In turn, Na-acamprosate and SIB-1893 had no direct effects on NMDA-induced neurotoxicity.
    Conclusions: Na-acamprosate demonstrates the binding and functional characteristics that are consistent with a group I mGluR antagonist. The functional similarities between Na-acamprosate and SIB-1893 support an interaction of Na-acamprosate at mGluR5s. The neuroprotective properties of acamprosate and possibly its ability to reduce craving in alcohol-dependent patients may result from its alterations in glutamatergic transmission through mGluRs.
    MeSH term(s) Animals ; Binding Sites/drug effects ; Binding Sites/physiology ; Cycloleucine/analogs & derivatives ; Cycloleucine/antagonists & inhibitors ; Cycloleucine/metabolism ; Cycloleucine/toxicity ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/metabolism ; Excitatory Amino Acid Antagonists/pharmacology ; Male ; Protein Binding/drug effects ; Protein Binding/physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Metabotropic Glutamate/antagonists & inhibitors ; Receptors, Metabotropic Glutamate/metabolism ; Taurine/analogs & derivatives ; Taurine/metabolism ; Taurine/pharmacology
    Chemical Substances Excitatory Amino Acid Antagonists ; Receptors, Metabotropic Glutamate ; Cycloleucine (0TQU7668EI) ; 1-amino-1,3-dicarboxycyclopentane (111900-32-4) ; Taurine (1EQV5MLY3D) ; acamprosate (N4K14YGM3J)
    Language English
    Publishing date 2002-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 428999-7
    ISSN 1530-0277 ; 0145-6008
    ISSN (online) 1530-0277
    ISSN 0145-6008
    DOI 10.1097/01.ALC.0000042011.99580.98
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