Distinct Effects of Olanzapine Depot Treatment on Behavior and Muscarinic M1 Receptor Expression in the Triple-Hit Wisket Rat Model of Schizophrenia

Abstract

This study aimed to characterize the triple-hit schizophrenia-like model rats (Wisket) by the assessment of (1) behavioral parameters in different test conditions (reward-based Ambitus test and HomeManner system) for a prolonged period, (2) cerebral muscarinic M1 receptor (M1R) expression, and (3) the effects of olanzapine treatment on these parameters. Wistar (control) and Wisket rats were injected for three consecutive weeks with olanzapine depot (100 mg/kg) and spent 4 weeks in large cages with environmental enrichment (HomeManner). The vehicle-treated Wisket rats spent longer time awake with decreased grooming activity compared to controls, without changes in their active social behavior (sniffing, playing, fighting) obtained in HomeManner. Olanzapine treatment decreased most of these parameters, only the passive social interaction (huddling during sleeping) enhanced mostly in the Wisket rats on the injection day, which recovered within 4 days. In the Ambitus test, vehicle-treated Wisket rats showed lower locomotor and exploratory activities and impaired cognition compared to control rats, deteriorating by olanzapine in both groups. In Wisket brain samples, the M1R mRNA expression was significantly lower in the cerebral cortex and elevated in the hippocampus, with no difference in the prefrontal cortex versus control. Olanzapine normalized the hippocampal M1R expression, but enhanced it in the prefrontal cortex. The triple-hit Wisket model rats had impaired behavioral characteristics in both acute reward-based test and undisturbed circumstances investigated for prolonged periods, and altered cerebral M1R expression. Chronic olanzapine treatment resulted deterioration of some parameters in control group, and could restore only few negative signs in model rats.