THE NEURONAL CIRCUITS IMPLICATED IN THE PHENCYCLIDINE-INDUCED BEHAVIORAL IMPAIRMENTS AND THERAPEUTIC AND SIDE EFFECTS OF ARIPIPRAZOLE
*Ami Ono, D. Koan, S. Asano, Tatsunori Miyaoka, Lu Chen, S. Nakagawa, Atsuko Hayata-Takano, Takanobu Nakazawa, Akihiro Harada, Hitoshi Hashimoto, James A. Waschek, Kotaro Tanimoto, Yukio Ago
International Journal of Neuropsychopharmacology February 1, 2025 DOI: 10.1093/ijnp/pyae059.309 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | ddY mice treated with phencyclidine to model schizophrenia |
| Interventions | Phencyclidine Aripiprazole |
| Dose | Phencyclidine: not stated; Aripiprazole: 0.3 mg/kg and 3.0 mg/kg |
| Duration | Phencyclidine injected for 14 consecutive days |
| Key findings | Aripiprazole at 0.3 mg/kg improved PCP-induced behavioral changes and attenuated decreased functional connectivity, whereas aripiprazole at 3.0 mg/kg induced catalepsy-like behavior and further increased functional connectivity. The authors suggest these effects reflect attenuation of dopaminergic dysfunction at low dose versus excessive dopamine D2 receptor antagonism at high dose. |
Abstract
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.