title: Probing the modulation of acute ethanol intoxication by pharmacological manipulation of the NMDAR glycine co-agonist site.
abstract: BACKGROUND
  Stimulating the glycine(B)  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 glycine(B)  agonist, d-serine, the GlyT-1 glycine transporter inhibitor, ALX-5407, and the glycine(B)  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 glycine(B)  partial agonist, d-cycloserine (DCS), the GlyT-1 inhibitor, N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS), and the glycine(B)  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 glycine(B)  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
  Glycine(B)  site activation failed to produce the hypothesized reduction in EtOH intoxication across a range of measures and genetic strains, but blockade of the glycine(B)  site potentiated EtOH intoxication. These data suggest endogenous activity at the glycine(B)  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 glycine(B)  site.
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience , National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, Maryland, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Debrouse
authors.forename: Benita
authors.initials: B
authors.lastname: Hurd
authors.forename: Carly
authors.initials: C
authors.lastname: Kiselycznyk
authors.forename: Aaron
authors.initials: A
authors.lastname: Plitt
authors.forename: Alyssa
authors.initials: A
authors.lastname: Todaro
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
authors.forename: Marguerite
authors.initials: M
authors.lastname: Camp
authors.forename: Ozge
authors.initials: O
authors.lastname: Gunduz-Cinar
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000435:Alcoholic Intoxication / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000188:drug therapy; D003523:Cycloserine / Q000494:pharmacology; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D051528:Guanylate Kinases / Q000235:genetics; D007035:Hypothermia / Q000139:chemically induced / Q000188:drug therapy; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008274:Magnesium / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018009:Receptors, Glycine / Q000819:agonists* / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D057897:Reflex, Righting / Q000187:drug effects; D012521:Sarcosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D012694:Serine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D003523:Cycloserine; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate; D050487:Glycine Plasma Membrane Transport Proteins; D051528:Guanylate Kinases; D007736:Kynurenic Acid; D008274:Magnesium; D008565:Membrane Proteins; D015363:Quinolones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D012521:Sarcosine; D012694:Serine; C510369:(R)-(N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl))sarcosine; C501447:Dlg4 protein, mouse; C491949:Glrb protein, mouse; C435025:N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine; C493267:Slc6a9 protein, mouse; C094635:L 701324; C066192:5,7-dichlorokynurenic acid