Recently, it has been proposed that activation of either
metabotropic glutamate receptors e.g. mGlu(5) by positive allosteric modulators or stimulation of mGluR(2/3) receptors by agonists may offer new strategy in
schizophrenia treatment. The aim of the present study was to compare the effect of mGlu(5) receptor positive allosteric modulator,
ADX47273 (S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone), mGluR(2/3) 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 10mg/kgi.p.), the typical
antipsychotic haloperidol (0.1 and 0.2mg/kgi.p.), the atypical
antipsychotics aripiprazole (1.25-5mg/kgi.p.) and
olanzapine (2.5 and 5mg/kgi.p.) all reduced
amphetamine-induced hyperlocomotion in Sprague-Dawley rats, unlike the mGlu(2/3) receptor agonist
LY354740 (1-10mg/kgi.p.). Interestingly,
haloperidol (0.1 and 0.2mg/kgi.p.),
aripiprazole (1.25-5mg/kgi.p.) and
olanzapine (1.25-5mg/kgi.p.), but not
ADX47273 (1-10mg/kgi.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 (30mg/kgi.p.),
haloperidol (0.1 and 0.2mg/kgi.p.) and
aripiprazole (5 and 10mg/kgi.p.) reversed
apomorphine (0.5mg/kgs.c.)-induced deficits of prepulse inhibition, whereas neither
LY354740 (1-10mg/kgi.p.) nor
olanzapine (1.25-5mg/kgi.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.