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Probing the Modulation of Acute Ethanol Intoxication by Pharmacological Manipulation of the NMDAR Glycine Co-Agonist Site

Research output: Contribution to journalArticle

  • Lauren DeBrouse
  • Benita Hurd
  • Carly Kiselycznyk
  • Aaron Plitt
  • Alyssa Todaro
  • Masayoshi Mishina
  • Seth G. N. Grant
  • Marguerite Camp
  • Ozge Gunduz-Cinar
  • Andrew Holmes

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    Rights statement: Published in final edited form as: Alcohol Clin Exp Res. Feb 2013; 37(2): 223–233.

    Accepted author manuscript, 1 MB, PDF-document

http://onlinelibrary.wiley.com/doi/10.1111/j.1530-0277.2012.01922.x/abstract;jsessionid=DD99495165A2D9153205754DF94F05B9.f03t03
Original languageEnglish
Pages (from-to)223-233
Number of pages11
JournalAlcoholism-Clinical and experimental research
Volume37
Issue number2
DOIs
Publication statusPublished - Feb 2013

Abstract

Background
Stimulating the glycineB binding site on the N-methyl-d-aspartate ionotropic glutamate receptor (NMDAR) has been proposed as a novel mechanism for modulating behavioral effects of ethanol (EtOH) that are mediated via the NMDAR, including acute intoxication. Here, we pharmacologically interrogated this hypothesis in mice.
Methods
Effects of systemic injection of the glycineB agonist, d-serine, the GlyT-1 glycine transporter inhibitor, ALX-5407, and the glycineB antagonist, L-701,324, were tested for the effects on EtOH-induced ataxia, hypothermia, and loss of righting reflex (LORR) duration in C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mice. Effects of the glycineB partial agonist, d-cycloserine (DCS), the GlyT-1 inhibitor, N-[3-(4-fluorophenyl)-3-(4-phenylphenoxy)propyl]sarcosine (NFPS), and the glycineB antagonist, 5,7-dichlorokynurenic (DCKA), on EtOH-induced LORR duration were also tested. Interaction effects on EtOH-induced LORR duration were examined via combined treatment with d-serine and ALX-5407, d-serine and MK-801, d-serine and L-701,324, as well as L-701,324 and ALX-5407, in B6 mice, and d-serine in GluN2A and PSD-95 knockout mice. The effect of dietary depletion of magnesium (Mg), an element that interacts with the glycineB site, was also tested.
Results
Neither d-serine, DCS, ALX-5407, nor NFPS significantly affected EtOH intoxication on any of the measures or strains studied. L-701,324, but not DCKA, dose-dependently potentiated the ataxia-inducing effects of EtOH and increased EtOH-induced (but not pentobarbital-induced) LORR duration. d-serine did not have interactive effects on EtOH-induced LORR duration when combined with ALX-5407. The EtOH-potentiating effects of L-701,324, but not MK-801, on LORR duration were prevented by d-serine, but not ALX-5407. Mg depletion potentiated LORR duration in B6 mice and was lethal in a large proportion of S1 mice.
Conclusions
GlycineB site activation failed to produce the hypothesized reduction in EtOH intoxication across a range of measures and genetic strains, but blockade of the glycineB site potentiated EtOH intoxication. These data suggest endogenous activity at the glycineB opposes EtOH intoxication, but it may be difficult to pharmacologically augment this action, at least in nondependent subjects, perhaps because of physiological saturation of the glycineB site.

    Research areas

  • RECEPTOR ANTAGONISTS, Alcohol, d-Serine, IMPAIRED FEAR EXTINCTION, SEEKING BEHAVIOR, IN-VIVO, METHYL-D-ASPARTATE, D-CYCLOSERINE, BINDING-SITES, Zinc, RAPID TOLERANCE, Glutamate, Magnesium, HIPPOCAMPAL-NEURONS, MEDIATED RESPONSES

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