Comparison of c-Fos induction in the brain by the mGlu2/3 receptor antagonist LY341495 and agonist LY354740: Evidence for widespread endogenous tone at brain mGlu2/3 receptors in vivo

LY341495 and LY354740 are potent and selective antagonist and agonist, respectively, for Group II metabotropic glutamate (mGlu2/3) receptors. Here we demonstrate that LY341495 (3 mg/kg) significantly increased c-Fos expression in almost all brain regions analyzed (44 out of 52 regions) in animals th...

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Veröffentlicht in:Neuropharmacology 2005, Vol.49, p.120-134
Hauptverfasser: Linden, A.-M., Bergeron, M., Schoepp, D.D.
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Schoepp, D.D.
description LY341495 and LY354740 are potent and selective antagonist and agonist, respectively, for Group II metabotropic glutamate (mGlu2/3) receptors. Here we demonstrate that LY341495 (3 mg/kg) significantly increased c-Fos expression in almost all brain regions analyzed (44 out of 52 regions) in animals that were prehandled and kept in home-cage environment to minimize stress. Robust c-Fos induction was observed in all cortical regions, hippocampal CA1 and CA3 subregions, amygdala and several other subcortical nuclei. In contrast to LY341495, changes in c-Fos expression following LY354740 were more modest and not generally widespread (decreased in 1 region, dentate gyrus; and increased in 13 out of 52 regions). Interestingly, although LY354740 is anxiolytic in animals, LY341495 did not increase c-Fos expression in the paraventricular nucleus of the hypothalamus which is usually activated by stress/fear and several anxiogenic compounds. To further investigate the behavioral consequences of mGlu2/3 receptor antagonism, LY341495 was administered to prehandled animals that were placed in the elevated plus maze test under low light (low stress) conditions. Here LY341495 increased mouse elevated plus maze (EPM)-anxiety in a dose-dependent manner, significantly decreasing the time spent in open arms, but not affecting total ambulations. The behavioral consequences and associated widespread pattern of brain neuronal activations following blockade of mGlu2/3 receptors suggest that there is considerable endogenous glutamate tone throughout the brain at negative feedback peri-synaptic mGlu2/3 receptors, even under low stress conditions where synaptic glutamate release spillover would be expected to be minimized.
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Bergeron, M. ; Schoepp, D.D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c403t-dc9ed764c56399522d693f9081f890afd95ea6d1e10c4e067a538e568cdd9a2b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Amino Acids - pharmacology</topic><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Brain - cytology</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Bridged Bicyclo Compounds - pharmacology</topic><topic>c-Fos</topic><topic>Cell Count - methods</topic><topic>Central nucleus of the amygdala</topic><topic>Dose-Response Relationship, Drug</topic><topic>Excitatory Amino Acid Agonists - pharmacology</topic><topic>Excitatory Amino Acid Antagonists - pharmacology</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Hippocampus</topic><topic>Immunohistochemistry - methods</topic><topic>LY341495</topic><topic>LY354740</topic><topic>Male</topic><topic>Metabotropic glutamate receptors</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Proto-Oncogene Proteins c-fos - metabolism</topic><topic>Xanthenes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Linden, A.-M.</creatorcontrib><creatorcontrib>Bergeron, M.</creatorcontrib><creatorcontrib>Schoepp, D.D.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Neuropharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Linden, A.-M.</au><au>Bergeron, M.</au><au>Schoepp, D.D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparison of c-Fos induction in the brain by the mGlu2/3 receptor antagonist LY341495 and agonist LY354740: Evidence for widespread endogenous tone at brain mGlu2/3 receptors in vivo</atitle><jtitle>Neuropharmacology</jtitle><addtitle>Neuropharmacology</addtitle><date>2005</date><risdate>2005</risdate><volume>49</volume><spage>120</spage><epage>134</epage><pages>120-134</pages><issn>0028-3908</issn><eissn>1873-7064</eissn><abstract>LY341495 and LY354740 are potent and selective antagonist and agonist, respectively, for Group II metabotropic glutamate (mGlu2/3) receptors. 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subjects Amino Acids - pharmacology
Analysis of Variance
Animals
Brain - cytology
Brain - drug effects
Brain - metabolism
Bridged Bicyclo Compounds - pharmacology
c-Fos
Cell Count - methods
Central nucleus of the amygdala
Dose-Response Relationship, Drug
Excitatory Amino Acid Agonists - pharmacology
Excitatory Amino Acid Antagonists - pharmacology
Gene Expression Regulation - drug effects
Hippocampus
Immunohistochemistry - methods
LY341495
LY354740
Male
Metabotropic glutamate receptors
Mice
Mice, Inbred ICR
Neurons - drug effects
Neurons - metabolism
Proto-Oncogene Proteins c-fos - metabolism
Xanthenes - pharmacology
title Comparison of c-Fos induction in the brain by the mGlu2/3 receptor antagonist LY341495 and agonist LY354740: Evidence for widespread endogenous tone at brain mGlu2/3 receptors in vivo
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