Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics
- Andrea M. BradfordAffiliated withBiology Department, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline plc
- , Kevin M. SavageAffiliated withResearch and Development Information Technology, GlaxoSmithKline plc
- , Declan N. C. JonesAffiliated withEuropean Centre of Excellence for External Drug Discovery, GlaxoSmithKline plc
- , Mikhail KalinichevAffiliated withCNS Business Unit, Addex Pharmaceuticals, Bâtiment A&C, Immeuble Alliance Email author
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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.
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).
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 (D1 antagonist), sulpiride (D2/D3 antagonist), raclopride (D2/D3 antagonist), SB-277011 (D3 antagonist), L-745,870 (D4 antagonist), WAY100635 (5-HT1A antagonist), 8-OH-DPAT (5-HT1A agonist), ketanserin (5-HT2A/5-HT2C antagonist) and SB-242084 (5-HT2C antagonist). In study 3, we tested xanomeline (M1/M4 receptor agonist), LY379268 (mGluR2/3 receptor agonist), diazepam (GABAA modulator) and thioperamide (H3 receptor antagonist).
All antipsychotics suppressed MK-801-induced hyperactivity in a dose-dependent and specific manner. The effects of antipsychotics appear to be mediated via dopamine D1, D2 and 5-HT2 receptors. Xanomeline, LY379268 and diazepam were active in this assay while thioperamide was not.
MK-801-induced hyperactivity in BALB/C mice model of positive symptoms has shown predictive validity with novel compounds acing at M1/M4, mGluR2/3 and GABAA receptors and can be used as a screening assay for detection of novel pharmacotherapies targeting those receptors.
KeywordsGlutamate MK-801 Schizophrenia Locomotor activity Hyperactivity Antipsychotic
- Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics
Volume 212, Issue 2 , pp 155-170
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- 1. Biology Department, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline plc, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
- 2. Research and Development Information Technology, GlaxoSmithKline plc, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
- 3. European Centre of Excellence for External Drug Discovery, GlaxoSmithKline plc, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
- 4. CNS Business Unit, Addex Pharmaceuticals, Bâtiment A&C, Immeuble Alliance, 74160, Archamps, France