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Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics

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Abstract

Rationale

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.

Objectives

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 (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).

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 D1, D2 and 5-HT2 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 M1/M4, mGluR2/3 and GABAA receptors and can be used as a screening assay for detection of novel pharmacotherapies targeting those receptors.

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  1. Declan N. C. Jones

    Present address: European Centre of Excellence for External Drug Discovery, GlaxoSmithKline plc, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK

  2. Mikhail Kalinichev

    Present address: CNS Business Unit, Addex Pharmaceuticals, Bâtiment A&C, Immeuble Alliance, 74160, Archamps, France

Authors and Affiliations

  1. Biology Department, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline plc, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK

    Andrea M. Bradford

  2. Research and Development Information Technology, GlaxoSmithKline plc, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK

    Kevin M. Savage

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Bradford, A.M., Savage, K.M., Jones, D.N.C. et al. Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics. Psychopharmacology 212, 155–170 (2010). https://doi.org/10.1007/s00213-010-1938-0

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