title: Group 1 mGlu-family proteins promote neuroadaptation to ethanol and withdrawal-associated hippocampal damage.
abstract: BACKGROUND
  Group 1 mGlu-family proteins (i.e., mGlu) consist of mGlu1 and mGlu5 and their activity may influence voluntary ethanol intake. The present studies sought to examine the influence of these receptors on the development of ethanol dependence using in vitro and in vivo models of chronic, intermittent ethanol (CIE).
  
  
  METHODS
  Rat hippocampal explants were exposed to CIE with or without the addition of mGlu1 antagonist (7-hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt; 0.5, 1, and 3μM) or mGlu5 antagonist (E)-2-methyl-6-styryl-pyridine (SIB-1893; 20, 100, and 200μM) to assess sparing of withdrawal-induced cytotoxicity. In a separate study, adult male rats were administered CIE with or without the addition of oral administration of group 1 mGlu antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP; 3mg/kg). Blood ethanol levels (BELs) were determined at 0930h on Day 2 of Weeks 1, 2, and 3. Withdrawal behavior was monitored during Day 6 of the third consecutive withdrawal.
  
  
  RESULTS
  CIE produced significant hippocampal cytotoxicity. These effects were attenuated by co-exposure to CPCCOEt (3μM) with ethanol in the CA3. By contrast, these effects were blocked by SIB-1893 (20μM) in each primary cell layer. Oral administration of MPEP with ethanol significantly attenuated behavioral effects of subsequent withdrawal and reduced BELs.
  
  
  CONCLUSIONS
  These data demonstrate that ethanol activates group 1 mGlu-family proteins to promote withdrawal-associated cytotoxicity in vitro and physical dependence in vivo. These findings suggest that group 1 mGlu-family proteins may be therapeutic targets for treatment of alcohol use disorders.
authors.affiliation: University of Kentucky, Department of Behavioral Science, United States. Electronic address: anna.reynolds@uky.edu.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Reynolds
authors.affiliation: University of Kentucky, Department of Psychology, United States; University of Kentucky, Spinal Cord and Brain Injury Research Center, United States.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Williams
authors.affiliation: University of Kentucky, Department of Psychology, United States; University of Kentucky, Spinal Cord and Brain Injury Research Center, United States.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Saunders
authors.affiliation: University of Kentucky, Department of Psychology, United States; University of Kentucky, Spinal Cord and Brain Injury Research Center, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Prendergast
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D063425:Binge Drinking / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000473:pathology; D002492:Central Nervous System Depressants / Q000097:blood / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D006624:Hippocampus / Q000473:pathology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000235:genetics*; D013375:Substance Withdrawal Syndrome / Q000235:genetics* / Q000473:pathology* / Q000523:psychology
chemical_list: C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D002492:Central Nervous System Depressants; D002867:Chromones; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C120148:SIB 1893; D000431:Ethanol
keywords: CIE; Chronic intermittent ethanol; Metabotropic glutamate receptor; NeuN; Neuron specific nuclear protein; mGlu