Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia.
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.
Robbins
Melanie J
MJ
Psychiatry 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>
Starr
Kathryn R
KR
Honey
Andy
A
Soffin
Ellen M
EM
Rourke
Claire
C
Jones
Gareth A
GA
Kelly
Fiona M
FM
Strum
Jay
J
Melarange
Rosemary A
RA
Harris
Andy J
AJ
Rocheville
Magalie
M
Rupniak
Tom
T
Murdock
Paul R
PR
Jones
Declan N C
DN
Kew
James N C
JN
Maycox
Peter R
PR
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D017660:Autoreceptors / Q000819:agonists / Q000096:biosynthesis / Q000502:physiology; D001565:Benzoates / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004597:Electroshock; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D012559:Schizophrenia / Q000378:metabolism* / Q000503:physiopathology; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects
C110733:3,4-dicarboxyphenylglycine; D000927:Anticonvulsants; D017660:Autoreceptors; D001565:Benzoates; D000697:Central Nervous System Stimulants; D018094:Receptors, Metabotropic Glutamate; C111435:metabotropic glutamate receptor 8; D000661:Amphetamine; D010622:Phencyclidine; D005998:Glycine