THE NEURONAL CIRCUITS IMPLICATED IN THE PHENCYCLIDINE-INDUCED BEHAVIORAL IMPAIRMENTS AND THERAPEUTIC AND SIDE EFFECTS OF ARIPIPRAZOLE

Abstract Background Schizophrenia is a psychiatric disorder characterized by positive and negative symptoms and cognitive impairments. Second-and third-generation antipsychotics alleviate not only positive symptoms but also negative symptoms and cognitive impairments, with a lower liability for extrapyramidal symptoms (EPS).Accumulating evidences suggest that dopaminergic mesocorticolimbic and nigrostriatal pathways implicated in the pathophysiology of schizophrenia and the therapeutic and side effects of antipsychotics. However, the detailed mechanism remains unclear. Aims & Objectives To explore them, we investigated the neuronal circuits implicated in the therapeutic and side effects of aripiprazole, a dopamine D2 receptor partial agonist, in the animal model of schizophrenia by using connectome analysis. Method A mouse model of schizophrenia was prepared by phencyclidine (PCP), s.c. injection to ddY mice for 14 consecutive days. Result Repeated PCP induced the sensitization of PCP-induced hyperactivity, social deficit and impairment of object recognition memory which associated with increase of dopamine turnover in the nucleus accumbens, but decreases of it in the prefrontal cortex. Aripiprazole (0.3mg/kg) improved these PCP- induced behavioral changes. However, aripiprazole (3.0mg/kg) induced catalepsy such as EPS-like behavior. Connectome analysis using MRI revealed that repeated PCP administration decreased functional connectivity, but aripiprazole (0.3mg/kg) attenuated it. However,aripiprazole (3.0mg/kg) further increased functional connectivity. Discussion & Conclusion These results suggest that aripiprazole (0.3mg/kg) improves PCP-induced behavioral changes and decreased functional connectivity by attenuating dopaminergic disfunction, but high-dose aripiprazole (3.0mg/kg) induces catalepsy associated with increased functional connectivity induced by excessive dopamine D2 receptor antagonism.