title: Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP.
abstract: The development of selective type 5 metabotropic glutamate receptor (mGlu5) antagonists, such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), has revealed an important role for these receptors in various disorders of the nervous system including depression, anxiety, epilepsy, Parkinson's disease, drug addiction, and alcoholism. In this study, we used microarray technology to examine changes in gene expression induced by repeated administration of the mGlu5 antagonists MPEP and MTEP. Male Wistar rats (n=5 per treatment group) were administered MPEP (10 mg/kg), MTEP (10 mg/kg) or vehicle intraperitoneally twice daily for 5 days. Approximately 30 min following the final drug administration, rats were sacrificed and frontal cortices were then dissected and examined for changes in gene expression by cDNA microarray analysis. Changes in gene expression with p-values less than 0.01 were considered to be statistically significant. The expression of 63 genes was changed by both MPEP and MTEP, with 58 genes down-regulated and 5 genes up-regulated. Quantitative PCR verified the magnitude and direction of change in expression of 9 of these genes (r2=0.556, p=0.017). Pathway analysis revealed that many of the biological processes altered by repeated MPEP and MTEP treatment were related to ATP synthesis, hydrolase activity, and signaling pathways associated with mitogen-activated protein kinase (MAPK). Our results demonstrate diverse effects of MPEP and MTEP gene expression in the frontal cortex, and these results may help elucidate the mechanisms by which these compounds produce beneficial effects in animal models of various disorders of the central nervous system.
authors.affiliation: Center for Drug and Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Gass
authors.forename: M Foster
authors.initials: MF
authors.lastname: Olive
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D016000:Cluster Analysis; D004734:Energy Metabolism / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006867:Hydrolases / Q000235:genetics; D007274:Injections, Intraperitoneal; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C121465:6-methyl-2-(phenylethynyl)pyridine; D000255:Adenosine Triphosphate; D006867:Hydrolases