title: Opposing efficacy of group III mGlu receptor activators, LSP1-2111 and AMN082, in animal models of positive symptoms of schizophrenia.
abstract: BACKGROUND
  Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new and efficient way to achieve antipsychotic-like activity.
  
  
  OBJECTIVE
  Here, we decided to investigate the possible role of the group III mGlu receptor ligands, LSP1-2111, the group III mGlu receptor orthosteric agonist, preferentially stimulating mGlu4 receptors especially in low doses, and AMN082, the mGlu7 receptor positive modulator. We used MK-801- and amphetamine-induced hyperactivity tests, as well as DOI-induced head twitches in mice as models for positive symptoms of psychosis. The C57Bl/6J mGlu7 receptor knockout mice were used to confirm that AMN082-induced effect was receptor specific. A non-selective antagonist of the group II/III mGlu receptors, LY341495, was used to block LSP1-2111-induced effects.
  
  
  RESULTS
  LSP1-2111 (1, 2, and 5 mg kg(-1)) dose dependently inhibited both MK-801- and amphetamine-induced hyperactivities. Moreover, the drug antagonized DOI-induced head twitches. The effects of the drug were antagonized by LY341495 administration (1.5 mg kg(-1), i.p.). In contrast, AMN082 (3 and 6 mg kg(-1)) had no effect on amphetamine-induced hyperactivity but induced an enhancement of MK-801-induced hyperactivity and DOI-induced head twitches in mice. In C57Bl/6J mGlu7 receptor knockout animals (KO), those effects of AMN082 were not observed. Moreover, mGlu7 KO animals were less sensitive for DOI-induced effect than their wild type littermates.
  
  
  CONCLUSIONS
  Altogether, we propose that among group III mGlu receptors, mGlu4 receptor may be a promising target for the development of novel antipsychotic drugs.
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, Poland. wierons@if-pan.krakow.pl
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wierońska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Stachowicz
authors.forename: Francine
authors.initials: F
authors.lastname: Acher
authors.forename: Tomasz
authors.initials: T
authors.lastname: Lech
authors.forename: Andrzej
authors.initials: A
authors.lastname: Pilc
mesh_terms: D000613:Aminobutyrates / Q000008:administration & dosage / Q000494:pharmacology*; D000662:Amphetamines / Q000633:toxicity; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000633:toxicity; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010721:Phosphinic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000613:Aminobutyrates; D000662:Amphetamines; D014150:Antipsychotic Agents; D001559:Benzhydryl Compounds; C555637:LSP1 2111; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D010721:Phosphinic Acids; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D016291:Dizocilpine Maleate; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D003913:Dextroamphetamine; C108823:metabotropic glutamate receptor 4