Group 1 mGlu-family proteins promote neuroadaptation to ethanol and withdrawal-associated hippocampal damage

Anna R. Reynolds, Luke A. Williams, Meredith A. Saunders, Mark A. Prendergast

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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 3 μM) or mGlu5 antagonist (E)-2-methyl-6-styryl-pyridine (SIB-1893; 20, 100, and 200 μM) 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; 3 mg/kg). Blood ethanol levels (BELs) were determined at 0930 h 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 (3 μM) with ethanol in the CA3. By contrast, these effects were blocked by SIB-1893 (20 μM) 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.

Original languageEnglish
Article number5748
Pages (from-to)213-220
Number of pages8
JournalDrug and Alcohol Dependence
Volume156
DOIs
StatePublished - Nov 1 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Ireland Ltd.

Keywords

  • CIE
  • Chronic intermittent ethanol
  • MGlu
  • Metabotropic glutamate receptor
  • NeuN
  • Neuron specific nuclear protein

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

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