1. Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics.
- Author
-
Bradford AM, Savage KM, Jones DN, and Kalinichev M
- Subjects
- Animals, Antipsychotic Agents administration & dosage, Dose-Response Relationship, Drug, Drug Delivery Systems, Hyperkinesis chemically induced, Hyperkinesis prevention & control, Male, Mice, Mice, Inbred BALB C, Receptors, GABA-A metabolism, Receptors, Metabotropic Glutamate drug effects, Receptors, Metabotropic Glutamate metabolism, Receptors, Muscarinic drug effects, Receptors, Muscarinic metabolism, Time Factors, Antipsychotic Agents pharmacology, Dizocilpine Maleate pharmacology, Excitatory Amino Acid Antagonists pharmacology, Motor Activity drug effects
- 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 โ= 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.
- Published
- 2010
- Full Text
- View/download PDF