Comparison of the mGlu5 receptor positive allosteric modulator ADX47273 and the mGlu2/3 receptor agonist LY354740 in tests for antipsychotic-like activity

Recently, it has been proposed that activation of either metabotropic glutamate receptors e.g. mGlu5 by positive allosteric modulators or stimulation of mGluR2/3 receptors by agonists may offer new strategy in schizophrenia treatment. The aim of the present study was to compare the effect of mGlu5 receptor positive allosteric modulator, ADX47273 (S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol—5-yl]-piperidin-1-yl}-methanone), mGluR2/3 agonist, LY354740 ((1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate) and selected neuroleptics in animal models for positive schizophrenia symptoms. ADX47273 (3 and 10 mg/kg i.p.), the typical antipsychotic haloperidol (0.1 and 0.2 mg/kg i.p.), the atypical antipsychotics aripiprazole (1.25–5 mg/kg i.p.) and olanzapine (2.5 and 5 mg/kg i.p.) all reduced amphetamine-induced hyperlocomotion in Sprague–Dawley rats, unlike the mGlu2/3 receptor agonist LY354740 (1–10 mg/kg i.p.). Interestingly, haloperidol (0.1 and 0.2 mg/kg i.p.), aripiprazole (1.25–5 mg/kg i.p.) and olanzapine (1.25–5 mg/kg i.p.), but not ADX47273 (1–10 mg/kg i.p.), all reduced spontaneous locomotion and rearings at doses effective against amphetamine-induced hyperlocomotion. This indicates that the effect of ADX47273 in combination with amphetamine may be specific, and also suggests a lack of sedative side effects. Moreover, ADX47273 (30 mg/kg i.p.), haloperidol (0.1 and 0.2 mg/kg i.p.) and aripiprazole (5 and 10 mg/kg i.p.) reversed apomorphine (0.5 mg/kg s.c.)-induced deficits of prepulse inhibition, whereas neither LY354740 (1–10 mg/kg i.p.) nor olanzapine (1.25–5 mg/kg i.p.) produced this effect. Lack of effect of olanzapine was unexpected and at present no convincing explanation can be provided. In conclusion, in selected rodent models for positive schizophrenia symptoms, ADX47273 showed better efficacy than LY354740.