EFFECT OF CLOZAPINE ON NEUROCOGNITIVE AND SOCIAL COGNITIVE FUNCTIONS IN A SCHIZOPHRENIA-LIKE MOUSE MODEL
Authors: Kawai *Shunya , Yoshimi Akira , Kato Ayaka , Uchida Mizuki , Kitagaki Shinji , Ozaki Norio , Noda Yukihiro 
Published: February 2025

Abstract

Background
Schizophrenia is a chronic psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive dysfunction. In particular, neurocognitive and social cognitive deficits have negative consequences on functional capacity or community functioning, and then a significant reduced the quality of life. Nonetheless, antipsychotics are limited as they provide only minimal ameliorating efficacy on cognitive performance. Clozapine (CLZ), an atypical antipsychotic, has remarkable effectiveness for treatment-resistant schizophrenia, as a result patients were provided.
However, the effects of CLZ on neurocognitive and social cognitive functions and its molecular mechanisms remain unclear.

Objective
This study aims to investigate the effects of CLZ on neurocognitive and social cognitive behaviors in phencyclidine (PCP) administered mouse repeastedly, as a schizophrenia-like mouse model, or subsequently mouse treated with CLZ. In addition, we determined whether changes in neurotransmitters associated with these behaviors.

Methods
PCP (10 mg/kg, s.c.) or saline (10 mL/kg, s.c.) was injected once a day for 14 consecutive days to the 6-week-old male ICR strain mice. CLZ (10 mg/kg or 30 mg/kg, p.o.) or vehicle (10 mL/kg, p.o.) was treated once a day for 7 consecutive days from the next day of the final PCP or saline administration. Twenty-four hours after the last administration, the novel object recognition test and the 3-chamber social behavior test were performed sequentially. For the measurement of the contents of monoamines and their metabolites, the prefrontal cortex (PFC), nucleus accumbens (NAc), striatum (STR), hippocampus (HIP), and amygdala (AMY) were collected 24 hours after the last administration and quantified by using high-performance liquid chromatography.

Results
The mice administered PCP exhibited impairment in the object recognition. These neurocognitive impairments deficits were ameliorated by administration of CLZ (10 mg/kg and 30 mg/kg) repeatedly. In the 3-chamber social behavior test, PCP-administered mice exhibited sociability, as similar to the saline- administered control mice, but social novelty was impaired. The impairment of social novelty was by the administration of CLZ (10mg/kg) repeatedly. The levels of monoamines and their metabolites in the brains of PCP-treated mice did not show any significant changes across all regions. In PCP-administered mice, administration of CLZ (10 mg/kg) resulted in an increase in noradrenaline content in the NAc and a decrease in serotonin and its metabolite levels in the HIP. Furthermore, CLZ (30 mg/kg) administration induced the enhanced dopamine metabolism in the PFC and reduced dopamine metabolism in the NAc.

Discussion And Conclusion
PCP administration induced the impaired neurocognitive and social cognitive function. These behavioral impairments were attenuated by the subsequent administration of CLZ repeatedly. It is suggested that the brain region-specific monoaminergic systems is associated as attenuating mechanism of CLZ on cognitive impairments. Given the varying responses based on CLZ dosage and brain regions, further investigations are needed to elucidate the relationship between changes in monoamines in each brain region and cognitive impairments.