title: Activation of mGluR2/3 following stress hormone exposure restores sensitivity to alcohol in rats.
abstract: Sensitivity to the interoceptive effects of alcohol is blunted following a period of exposure to the stress hormone corticosterone (CORT), an effect that is suggested to be related, in part, to glutamatergic neuroadaptations. Group II metabotropic glutamate receptors (subtypes 2 and 3; mGluR2/3) modulate several drug- and alcohol-related behaviors, including the interoceptive (discriminative stimulus) effects of alcohol. Therefore, we sought to determine if manipulation of mGluR2/3 would restore sensitivity to the interoceptive effects of alcohol following CORT exposure. Using a two-lever drug discrimination task, male Long-Evans rats were trained to discriminate alcohol (1 g/kg, intragastric [IG]) vs. water. First, the effect of mGluR2/3 antagonism on the discriminative stimulus effects of alcohol was determined using LY341495 (0.3-3.0 mg/kg; intraperitoneal [IP]). Next, the effects of mGluR2/3 antagonism and activation were assessed in discrimination-trained animals exposed to CORT (300 μg/mL) in the home cage drinking water or water only, for 7 days. Following CORT exposure, decreased sensitivity to alcohol (1 g/kg) was observed. Pretreatment with the mGluR2/3 agonist LY379268 (1.0-3.0 mg/kg; IP), but not the mGluR2/3 antagonist (0.3-1.0 mg/kg; IP), restored sensitivity to alcohol. Additionally, in water controls, mGluR2/3 antagonism and mGluR2/3 activation disrupted expression of the discriminative stimulus effects of alcohol. Together, these findings suggest that blunted sensitivity to the interoceptive effects of alcohol following an episode of heightened stress hormone levels may be due to adaptations in mGluR2/3-related systems. The ability of mGluR2/3 activation to restore sensitivity to alcohol under these conditions lends further support for the importance of these receptors under stress-related conditions.
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Anel A
authors.initials: AA
authors.lastname: Jaramillo
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Randall
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Frisbee
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Kristen R
authors.initials: KR
authors.lastname: Fisher
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: jbesheer@med.unc.edu.
authors.forename: Joyce
authors.initials: J
authors.lastname: Besheer
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism* / Q000523:psychology; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003345:Corticosterone / Q000008:administration & dosage*; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012646:Self Administration; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C114624:LY 341495; C118218:LY 379268; D018091:Receptors, AMPA; D014966:Xanthenes; C104723:glutamate receptor ionotropic, AMPA 3; D000431:Ethanol; C104722:glutamate receptor ionotropic, AMPA 2; D003345:Corticosterone
keywords: Corticosterone; Drinking; LY341495; LY379268; Stress; mGluR2/3