title: Presynaptic, release-regulating mGlu2 -preferring and mGlu3 -preferring autoreceptors in CNS: pharmacological profiles and functional roles in demyelinating disease.
abstract: OBJECTIVE
  Presynaptic, release-regulating metabotropic glutamate 2 and 3 (mGlu2/3) autoreceptors exist in the CNS. They represent suitable targets for therapeutic approaches to central diseases that are typified by hyperglutamatergicity. The availability of specific ligands able to differentiate between mGlu2 and mGlu3 subunits allows us to further characterize these autoreceptors. In this study we investigated the pharmacological profile of mGlu2/3 receptors in selected CNS regions and evaluated their functions in mice with experimental autoimmune encephalomyelitis (EAE).
  
  
  METHODS
  The comparative analysis of presynaptic mGlu2/3 autoreceptors was performed by determining the effect of selective mGlu2/3 receptor agonist(s) and antagonist(s) on the release of [(3)H]-D-aspartate from cortical and spinal cord synaptosomes in superfusion. In EAE mice, mGlu2/3 autoreceptor-mediated release functions were investigated and effects of in vivo LY379268 administration on impaired glutamate release examined ex vivo.
  
  
  RESULTS
  Western blot analysis and confocal microscopy confirmed the presence of presynaptic mGlu2/3 receptor proteins. Cortical synaptosomes possessed LY541850-sensitive, NAAG-insensitive autoreceptors having low affinity for LY379268, while LY541850-insensitive, NAAG-sensitive autoreceptors with high affinity for LY379268 existed in spinal cord terminals. In EAE mice, mGlu2/3 autoreceptors completely lost their inhibitory activity in cortical, but not in spinal cord synaptosomes. In vivo LY379268 administration restored the glutamate exocytosis capability in spinal cord but not in cortical terminals in EAE mice.
  
  
  CONCLUSIONS
  We propose the existence of mGlu2-preferring and mGlu3-preferring autoreceptors in mouse cortex and spinal cord respectively. The mGlu3 -preferring autoreceptors could represent a target for new pharmacological approaches for treating demyelinating diseases.
authors.affiliation: Department of Pharmacy, DiFAR, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Prisco
authors.affiliation: Department of Pharmacy, DiFAR, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Merega
authors.affiliation: Department of Pharmacy, DiFAR, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Bonfiglio
authors.affiliation: Department of Pharmacy, DiFAR, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.
authors.forename: Guendalina
authors.initials: G
authors.lastname: Olivero
authors.affiliation: Department of Pharmacy, DiFAR, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cervetto
authors.affiliation: Department of Pharmacy, DiFAR, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Grilli
authors.affiliation: Institute of Biophysics, National Research Council, Genoa, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Usai
authors.affiliation: Department of Pharmacy, DiFAR, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.|Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Marchi
authors.affiliation: Department of Pharmacy, DiFAR, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.|Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pittaluga
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D017660:Autoreceptors / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017729:Presynaptic Terminals / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: C581970:2-amino-4-methylbicyclo(3.1.0)hexane2,6-dicarboxylic acid; D000600:Amino Acids, Dicarboxylic; D017660:Autoreceptors; D001643:Bridged Bicyclo Compounds; D004151:Dipeptides; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C027172:isospaglumic acid