Antischizophrenic effect of dopamine D3 receptor antagonist Y-QA31

OBJECTIVCE Schizophrenia is a chronic,debilitating psychotic mental disorder.Many studies suggest that dopamine D3 receptor(DAD3R) plays an important role in etioloy of schizophrenia,and selective DAD3R antagonists may have effects to improve the symptoms of schizophrenia.More important,the DAD3R antagonists result in less or no extrapyramidal side effect(EPS).Therefore,the present study is aimed to evaluate the pharmacological effects of Y-QA31 which was found to be a highly selective DAD3R antagonist,hoping to develop new potential APDs.METHODS We use the animals models,including methamphetamine(MA) or dizocilpine(MK-801) induced hyperactivity,apomorphine-induced climbing,the disruption of prepulse Inhibition elicited by MA,conditioned avoidance responding and apomorphine-induced hypothermia to evaluate the effects of Y-QA31 on the treatment of schizophrenia.Meanwhile,the induction of catalepsy of Y-QA31 was also observed in mice.RESULTS Y-QA31(20-40 mg·kg-1,po) effectively inhibited conditioned avoidance responding in mice,the hyperactivity induced by MA or MK-801,and apomorphine-induced hypothermia in mice by dose-dependence.Y-QA31(5 mg·kg-1,po) could also inhibit the reduction of prepulse Inhibition elicited by MA in mice.Morerover,Y-QA31(80 mg·kg-1,po) could also inhibit apomorphine-induced climbing in mice.Y-QA31 did not induce catalepsy when its dose increased to 200 mg·kg-1 po,suggesting the EPS of Y-QA31 was very low.CONCLUSIONThe above results indicated Y-QA31 exhibited the therapeutic effects on positive symptoms of schizophrenia with low EPS,and further suggested that DAD3R is the potential target in the treatment of schizophrenia.