title: The antipsychotic-like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents.
abstract: OBJECTIVE
  Because agonists at metabotropic glutamate receptors exert beneficial effects in schizophrenia, we have assessed the actions of Lu AF21934 and Lu AF32615, two chemically distinct, selective and brain-penetrant positive allosteric modulators (PAMs) of the mGlu4 receptor, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents.
  
  
  METHODS
  Hyperactivity induced by MK-801 or amphetamine and head twitches induced by 2,5-dimethoxy-4-iodoamphetamine (DOI) in mice were used as models for positive symptoms. Disruption of social interaction and spatial delayed alternation tests induced by MK-801 in rats were used as models for negative and cognitive symptoms of schizophrenia, respectively.
  
  
  RESULTS
  Lu AF21934 (0.1-5 mg·kg(-1) ) and Lu AF32615 (2-10 mg·kg(-1) ) dose-dependently inhibited hyperactivity induced by MK-801 or amphetamine. They also antagonized head twitches and increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in brain slices, induced by DOI. In mice lacking the mGlu4 receptor (mGlu4 (-/-) ) mice, Lu AF21934 did not antagonize DOI-induced head twitches. MK-801-induced disruption in the social interaction test was decreased by Lu AF21934 at 0.5 mg·kg(-1) and by Lu AF32615 at 10 mg·kg(-1) . In the delayed spatial alternation test, Lu AF21934 was active at 1 and 2 mg·kg(-1) , while Lu AF32615 was active at 10 mg·kg(-1) .
  
  
  CONCLUSIONS
  We propose that activation by PAMs of the mGlu4 receptor is a promising approach to the discovery of novel antipsychotic drugs.
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Sławińska
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wierońska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Stachowicz
authors.forename: Marcin
authors.initials: M
authors.lastname: Marciniak
authors.forename: Magdalena
authors.initials: M
authors.lastname: Lasoń-Tyburkiewicz
authors.forename: Piotr
authors.initials: P
authors.lastname: Gruca
authors.forename: Mariusz
authors.initials: M
authors.lastname: Papp
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kusek
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Tokarski
authors.forename: Darío
authors.initials: D
authors.lastname: Doller
authors.forename: Andrzej
authors.initials: A
authors.lastname: Pilc
mesh_terms: D000494:Allosteric Regulation; D000661:Amphetamine; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006948:Hyperkinesis / Q000188:drug therapy; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D000813:Anilides; D014150:Antipsychotic Agents; D003509:Cyclohexanecarboxylic Acids; C581971:N1-(3,4-dichlorophenyl)-cyclohexane-1,2-dicarboxamide; D018094:Receptors, Metabotropic Glutamate; D016291:Dizocilpine Maleate; D000661:Amphetamine
keywords: Lu AF21934; Lu AF32615; mGlu receptors; positive allosteric modulation; schizophrenia