title: 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: 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.
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky Chandler Medical Center, Lexington 40546, USA.
authors.forename: Barton R
authors.initials: BR
authors.lastname: Harris
authors.forename: D Alex
authors.initials: DA
authors.lastname: Gibson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Prendergast
authors.forename: John A
authors.initials: JA
authors.lastname: Blanchard
authors.forename: Robert C
authors.initials: RC
authors.lastname: Holley
authors.forename: Stewart R
authors.initials: SR
authors.lastname: Hart
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Scotland
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Foster
authors.forename: Norman W
authors.initials: NW
authors.lastname: Pedigo
authors.forename: John M
authors.initials: JM
authors.lastname: Littleton
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
chemical_list: D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate