title: Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics.
abstract: BACKGROUND
  We evaluated locomotor hyperactivity induced in BALB/C mice by an N-methyl-D-aspartate receptor antagonist MK-801 as an assay for the detection of antipsychotic drugs.
  
  
  OBJECTIVE
  We assessed the effects of antipsychotic drugs to validate the assay (study 1), selective dopamine and serotonin ligands for pharmacological characterisation of the model (study 2) and a number of compounds with efficacy in models of schizophrenia to understand the predictive validity of the model (study 3).
  
  
  METHODS
  Adult males (n  = 9/group) were pretreated with a test compound, habituated to locomotor activity cages before receiving MK-801 (0.32 mg/kg) and activity recorded for a further 75 or 120 min. In study 1, we tested haloperidol, clozapine, olanzapine, risperidone, ziprasidone, aripiprazole, sertindole and quetiapine. In study 2, we tested SCH23390 (D(1) antagonist), sulpiride (D(2)/D(3) antagonist), raclopride (D(2)/D(3) antagonist), SB-277011 (D(3) antagonist), L-745,870 (D(4) antagonist), WAY100635 (5-HT(1A) antagonist), 8-OH-DPAT (5-HT(1A) agonist), ketanserin (5-HT(2A)/5-HT(2C) antagonist) and SB-242084 (5-HT(2C) antagonist). In study 3, we tested xanomeline (M(1)/M(4) receptor agonist), LY379268 (mGluR2/3 receptor agonist), diazepam (GABA(A) modulator) and thioperamide (H(3) receptor antagonist).
  
  
  RESULTS
  All antipsychotics suppressed MK-801-induced hyperactivity in a dose-dependent and specific manner. The effects of antipsychotics appear to be mediated via dopamine D(1), D(2) and 5-HT(2) receptors. Xanomeline, LY379268 and diazepam were active in this assay while thioperamide was not.
  
  
  CONCLUSIONS
  MK-801-induced hyperactivity in BALB/C mice model of positive symptoms has shown predictive validity with novel compounds acing at M(1)/M(4), mGluR2/3 and GABA(A) receptors and can be used as a screening assay for detection of novel pharmacotherapies targeting those receptors.
authors.affiliation: Biology Department, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline plc, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Bradford
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Savage
authors.forename: Declan N C
authors.initials: DN
authors.lastname: Jones
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kalinichev
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006948:Hyperkinesis / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D011976:Receptors, Muscarinic; D016291:Dizocilpine Maleate