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

@article{citeulike:2968278, abstract = {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.}, author = {Robbins, Melanie J. and Starr, Kathryn R. and Honey, Andy and Soffin, Ellen M. and Rourke, Claire and Jones, Gareth A. and Kelly, Fiona M. and Strum, Jay and Melarange, Rosemary A. and Harris, Andy J. and Rocheville, Magalie and Rupniak, Tom and Murdock, Paul R. and Jones, Declan N. and Kew, James N. and Maycox, Peter R. }, citeulike-article-id = {2968278}, doi = {10.1016/j.brainres.2007.03.028}, journal = {Brain Research}, keywords = {grm8}, month = {June}, pages = {215--227}, posted-at = {2008-07-07 04:59:10}, priority = {2}, title = {Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia}, url = {http://dx.doi.org/10.1016/j.brainres.2007.03.028}, volume = {1152}, year = {2007} }

TY - JOUR ID - citeulike:2968278 L3 - citeulike-article-id:2968278 TI - Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia JF - Brain Research VL - 1152 SP - 215 EP - 227 N2 - 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. KW - grm8 AU - Robbins, Melanie AU - Starr, Kathryn AU - Honey, Andy AU - Soffin, Ellen AU - Rourke, Claire AU - Jones, Gareth AU - Kelly, Fiona AU - Strum, Jay AU - Melarange, Rosemary AU - Harris, Andy AU - Rocheville, Magalie AU - Rupniak, Tom AU - Murdock, Paul AU - Jones, Declan AU - Kew, James AU - Maycox, Peter PY - 2007/06/04/ UR - http://dx.doi.org/10.1016/j.brainres.2007.03.028 ER -