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Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia.

Authors: Robbins, MJ  Starr, KR  Honey, A  Soffin, EM  Rourke, C  Jones, GA  Kelly, FM  Strum, J  Melarange, RA  Harris, AJ  Rocheville, M  Rupniak, T  Murdock, PR  Jones, DN  Kew, JN  Maycox, PR 
Citation: Robbins MJ, etal., Brain Res. 2007 Jun 4;1152:215-27. Epub 2007 Mar 15.
Pubmed: (View Article at PubMed) PMID:17434465
DOI: Full-text: DOI:10.1016/j.brainres.2007.03.028

Aberrant glutamatergic neurotransmission may underlie the pathogenesis of schizophrenia and metabotropic glutamate receptors (mGluRs) have been implicated in the disease. We have established the localization of the group III mGluR subtype, mGluR8, in the human body and investigated the biological effects of the selective mGluR8 agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG) in schizophrenia-related animal models. The mGlu8 receptor has a widespread CNS distribution with expression observed in key brain regions associated with schizophrenia pathogenesis including the hippocampus. (S)-3,4-DCPG inhibited synaptic transmission and increased paired-pulse facilitation in rat hippocampal slices supporting the role of mGluR8 as a presynaptic autoreceptor. Using the rat Maximal Electroshock Seizure Threshold (MEST) test, (S)-3,4-DCPG (30 mg/kg, i.p.) reduced seizure activity confirming the compound to be centrally active following systemic administration. (S)-3,4-DCPG did not reverse (locomotor) hyperactivity induced by acute administration of phenylcyclidine (PCP, 1-32 mg/kg, i.p.) or amphetamine (3-30 mg/kg, i.p.) in Sprague-Dawley rats. However, 10 nmol (i.c.v.) (S)-3.4-DCPG did reverse amphetamine-induced hyperactivity in mice although it also inhibited spontaneous locomotor activity at this dose. In addition, mGluR8 null mutant mouse behavioral phenotyping revealed an anxiety-related phenotype but no deficit in sensorimotor gating. These data provide a potential role for mGluR8 in anxiety and suggest that mGluR8 may not be a therapeutic target for schizophrenia.

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CRRD Object Information
CRRD ID: 6771182
Created: 2012-07-16
Species: All species
Last Modified: 2012-07-16
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.