title: The antipsychotic-like effects of the mGlu group III orthosteric agonist, LSP1-2111, involves 5-HT₁A signalling.
abstract: BACKGROUND
  Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new way to achieve antipsychotic-like activity. LSP1-2111, the group III mGlu receptor orthosteric agonist, with a high affinity towards mGlu4 receptors, was previously shown to exhibit antipsychotic-like action in animal models displaying positive symptoms of schizophrenia.
  
  
  OBJECTIVE
  Here, we decided to investigate the possible role of LSP1-2111 in models of negative (social interaction) and cognitive (NOR) symptoms of psychosis. We also investigated the involvement of 5-HT1A receptors in the LSP1-2111-induced antipsychotic effects. Apart from the above-mentioned models of negative and cognitive symptoms, MK-801 and amphetamine-induced hyperactivity tests, plus the DOI-induced head twitches in mice as models for positive symptoms of psychosis, were used in this part of the investigations.
  
  
  RESULTS
  LSP1-2111 (0.5, 2, and 5 mg/ kg) dose-dependently inhibited MK-801-induced deficits in social interaction and NOR tests. The effects of the drug were antagonized by 5-HT1A antagonist, WAY100635 (0.1 mg/kg). A similar inhibition of LSP1-2111-induced effects was observed in models of positive symptoms of schizophrenia. Moreover, the concomitant administration of subeffective doses of LSP1-2111 (0.3-0.5 mg/kg) with a subeffective dose of 5-HT1A agonist, (R)-(+)-8-Hydroxy-DPAT (0.01 mg/kg), induced a clear antipsychotic-like effect in all of the procedures used.
  
  
  CONCLUSIONS
  Altogether, we propose that the activation of group III mGlu receptors may be a promising target for the development of novel antipsychotic drugs, towards not only positive but also negative and cognitive symptoms. The action of the compound is 5-HT1A-dependent.
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: Francine C
authors.initials: FC
authors.lastname: Acher
authors.forename: Anna
authors.initials: A
authors.lastname: Sławińska
authors.forename: Piotr
authors.initials: P
authors.lastname: Gruca
authors.forename: Magdalena
authors.initials: M
authors.lastname: Lasoń-Tyburkiewicz
authors.forename: Mariusz
authors.initials: M
authors.lastname: Papp
authors.forename: Andrzej
authors.initials: A
authors.lastname: Pilc
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000613:Aminobutyrates / Q000008:administration & dosage / Q000494:pharmacology*; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003510:Cyclohexanes / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D010721:Phosphinic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011618:Psychotic Disorders / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D015398:Signal Transduction
chemical_list: D000613:Aminobutyrates; D000662:Amphetamines; D014150:Antipsychotic Agents; D003510:Cyclohexanes; C555637:LSP1 2111; D010721:Phosphinic Acids; D010879:Piperazines; D018094:Receptors, Metabotropic Glutamate; C112802:WAY 101363; D044282:Receptor, Serotonin, 5-HT1A; D016291:Dizocilpine Maleate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D003913:Dextroamphetamine; C108823:metabotropic glutamate receptor 4