title: The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice.
abstract: Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1-/-mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1-/-mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function.
authors.affiliation: Department of Experimental Psychology, University of Oxford, 9 South Parks, Oxford, OX1 3UD, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Boerner
authors.affiliation: Department of Experimental Psychology, University of Oxford, 9 South Parks, Oxford, OX1 3UD, UK.
authors.forename: Alexei M
authors.initials: AM
authors.lastname: Bygrave
authors.affiliation: Department of Experimental Psychology, University of Oxford, 9 South Parks, Oxford, OX1 3UD, UK.
authors.forename: Jingkai
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Experimental Psychology, University of Oxford, 9 South Parks, Oxford, OX1 3UD, UK.
authors.forename: Anushka
authors.initials: A
authors.lastname: Fernando
authors.affiliation: Department of Experimental Psychology, University of Oxford, 9 South Parks, Oxford, OX1 3UD, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jackson
authors.affiliation: Department of Experimental Psychology, University of Oxford, 9 South Parks, Oxford, OX1 3UD, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Barkus
authors.affiliation: Max Planck Research Group, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.affiliation: Max Planck Research Group, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeburg
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Harrison
authors.affiliation: Lilly Centre for Cognitive Neuroscience, Discovery Biology, Lilly Research Centre, Lilly UK, Windlesham, Surrey, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Gilmour
authors.affiliation: Department of Experimental Psychology, University of Oxford, 9 South Parks, Oxford, OX1 3UD, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
authors.affiliation: Department of Psychology, Durham University, Science Site, South Road, Durham, DH1 3LE, UK.
authors.forename: David J
authors.identifier: 0000-0002-3560-5507
authors.initials: DJ
authors.lastname: Sanderson
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006220:Haloperidol / Q000494:pharmacology* / Q000627:therapeutic use; D006948:Hyperkinesis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D001643:Bridged Bicyclo Compounds; D018492:Dopamine Antagonists; D018690:Excitatory Amino Acid Agonists; D006220:Haloperidol; D018091:Receptors, AMPA; C104753:eglumetad
keywords: AMPA; Gria1; habituation; schizophrenia