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

Melanie J Robbins1, Kathryn R Starr, Andy Honey

  • 1Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park North, Harlow, Essex, UK. Melanie_j_robbins@gsk.com <Melanie_j_robbins@gsk.com>

Brain Research
|April 17, 2007
PubMed

Insights

Metabotropic glutamate receptor 8 (mGluR8) is present in the brain and acts as a presynaptic autoreceptor. While it shows potential in anxiety models, mGluR8 may not be a viable therapeutic target for schizophrenia.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Genetics

Background:

  • Aberrant glutamatergic neurotransmission is implicated in schizophrenia pathogenesis.
  • Metabotropic glutamate receptors (mGluRs), particularly group III mGluR8, are potential targets for neurological disorders.
  • Understanding mGluR8's role is crucial for developing novel therapeutic strategies.

Purpose of the Study:

  • To determine the localization and biological effects of the mGluR8 receptor and its selective agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG).
  • To investigate the potential of mGluR8 as a therapeutic target for schizophrenia using animal models.

Main Methods:

  • Localization studies of mGluR8 in the human body, focusing on CNS distribution.
  • (S)-3,4-DCPG administration in rat hippocampal slices to assess synaptic transmission and paired-pulse facilitation.
  • Behavioral assessments in rats and mice, including Maximal Electroshock Seizure Threshold (MEST) test, amphetamine/phenylcyclidine-induced hyperactivity, and locomotor activity.
  • Phenotyping of mGluR8 null mutant mice for anxiety-related behaviors and sensorimotor gating deficits.

Main Results:

  • mGluR8 is widely distributed in the CNS, including schizophrenia-associated brain regions like the hippocampus.
  • (S)-3,4-DCPG demonstrated presynaptic autoreceptor activity by inhibiting synaptic transmission and increasing paired-pulse facilitation in rat hippocampal slices.
  • (S)-3,4-DCPG exhibited central activity in rats, reducing seizure activity in the MEST test, but did not reverse PCP or amphetamine-induced hyperactivity.
  • While (S)-3,4-DCPG reversed amphetamine-induced hyperactivity in mice, it also inhibited spontaneous locomotor activity.
  • mGluR8 null mutant mice displayed an anxiety-related phenotype but no sensorimotor gating deficits.

Conclusions:

  • mGluR8 functions as a presynaptic autoreceptor in the hippocampus.
  • The study suggests a potential role for mGluR8 in anxiety regulation.
  • Current evidence indicates that mGluR8 may not be a suitable therapeutic target for schizophrenia.

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