TY - JOUR
T1 - Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP
AU - Gass, Justin T.
AU - Olive, M. Foster
N1 - Funding Information:
This study was supported by Public Health Service grant AA013852 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA, Bethesda, MD) to MFO, and an institutional training grant AA007474 (JTG). The authors wish to thank Dr. Jacqueline McGinty for her kind donation of the microarray chips, Victor Fresco of the MUSC DNA Microarray and Bioinformatics Facility for assistance in microarray hybridization procedures, and Robert Lee of Creative Biolabs Inc. for assistance in the analysis of the microarray data.
PY - 2008/4/28
Y1 - 2008/4/28
N2 - 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.
AB - 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.
KW - Antagonist
KW - Frontal cortex
KW - Gene expression
KW - Glutamate
KW - Hierarchical cluster analysis
KW - Microarray
KW - Pathway analysis
KW - Type 5 metabotropic glutamate receptor [mGlu5]
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U2 - 10.1016/j.ejphar.2008.02.032
DO - 10.1016/j.ejphar.2008.02.032
M3 - Article
C2 - 18346726
AN - SCOPUS:41249087635
SN - 0014-2999
VL - 584
SP - 253
EP - 262
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 2-3
ER -