title: The antipsychotic-like effects in rodents of the positive allosteric modulator Lu AF21934 involve 5-HT1A receptor signaling: mechanistic studies.
abstract: BACKGROUND
  Diverse preclinical studies suggest the potential therapeutic utility of the modulation of the glutamatergic system in brain via metabotropic glutamate (mGlu) receptors. Lu AF21934, a positive allosteric modulator of the mGlu4 receptor, was previously shown to reverse behavioral phenotypes in animal models thought to mimic positive, negative, and cognitive symptoms of schizophrenia.
  
  
  OBJECTIVE
  To begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT1A receptors in these antipsychotic-like effects was explored. The tests used were the following: MK-801-induced hyperactivity and 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitches in mice, for positive symptoms; MK-801-induced disruptions of social interactions for negative symptoms; and novel object recognition and spatial delayed alteration test for cognitive symptoms. The microdialysis studies in which the effect of Lu AF21934 on MK-801-induced dopamine and serotonin release was investigated.
  
  
  RESULTS
  The effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg). That inhibition was observed across all models used. Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT1A receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used. Lu AF21934 (5 mg/kg) also inhibited MK-801-induced increase in dopamine and 5-HT release.
  
  
  CONCLUSIONS
  The actions of Lu AF21934 are 5-HT1A receptor-dependent. Activation of the mGlu4 receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative, and cognitive symptoms.
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Smętna Str. 12, 31-343, Kraków, Poland, wierons@if-pan.krakow.pl.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wierońska
authors.forename: Anna
authors.initials: A
authors.lastname: Sławińska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Łasoń-Tyburkiewicz
authors.forename: Piotr
authors.initials: P
authors.lastname: Gruca
authors.forename: Mariusz
authors.initials: M
authors.lastname: Papp
authors.forename: Stevin H
authors.initials: SH
authors.lastname: Zorn
authors.forename: Darío
authors.initials: D
authors.lastname: Doller
authors.forename: Natalia
authors.initials: N
authors.lastname: Kłeczek
authors.forename: Karolina
authors.initials: K
authors.lastname: Noworyta-Sokołowska
authors.forename: Krystyna
authors.initials: K
authors.lastname: Gołembiowska
authors.forename: Andrzej
authors.initials: A
authors.lastname: Pilc
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*
chemical_list: D000813:Anilides; D014150:Antipsychotic Agents; D003509:Cyclohexanecarboxylic Acids; C581971:N1-(3,4-dichlorophenyl)-cyclohexane-1,2-dicarboxamide; D018094:Receptors, Metabotropic Glutamate; D044282:Receptor, Serotonin, 5-HT1A; D016291:Dizocilpine Maleate; C108823:metabotropic glutamate receptor 4