Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia
| Autor: | James N.C. Kew, Peter R. Maycox, Ellen M. Soffin, Rosemary A. Melarange, Andrew Jonathan Harris, Melanie J. Robbins, Claire Rourke, Jay Strum, Fiona M. Kelly, Magalie Rocheville, Gareth A. Jones, Declan N.C. Jones, Paul R. Murdock, Tom Rupniak, Andy Honey, Kathryn R. Starr |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Male
Agonist Psychosis medicine.drug_class Glycine Phencyclidine Anxiety Motor Activity Neurotransmission Pharmacology Receptors Metabotropic Glutamate Benzoates Synaptic Transmission Rats Sprague-Dawley Mice Seizures medicine Animals Humans Amphetamine Molecular Biology Autoreceptors Mice Knockout Electroshock Seizure threshold General Neuroscience Brain medicine.disease Rats Disease Models Animal Metabotropic glutamate receptor Dentate Gyrus Synapses Schizophrenia Autoreceptor Anticonvulsants Central Nervous System Stimulants Neurology (clinical) Psychology Neuroscience Developmental Biology medicine.drug |
| Zdroj: | Brain Research. 1152:215-227 |
| ISSN: | 0006-8993 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect