Antipsychotic activity of benzimidazole derivative RU-31 in rat models of psychosis

Schizophrenia is a complex mental disorder characterized by disturbances in cognitive functions, emotional regulation, and behavior. Selective 5-HT2A receptor antagonists are of particular interest as potential antipsychotic agents due to their more favorable safety profile compared to traditional neuroleptics.

Aim: To compare the neurophysiological and behavioral effects of the selective 5-HT2A receptor antagonist RU-31 and clozapine in ketamine and neonatal ventral hippocampal lesion (NVHL) models of schizophrenia.

Material and Methods. Adult male white rats weighing 250-290 g were used in the experiments. Local field potentials (LFP) were recorded in the medial prefrontal cortex (mPFC) and hippocampus (Hipp) following ketamine administration (20 mg/kg) and subsequent treatment with either clozapine (7,5 mg/kg) or RU-31 (10 mg/kg). Spectral analysis of the signals was performed. The weighted phase lag index (wPLI) was calculated to assess the functional connectivity between the mPFC and Hipp. Behavioral impairments were assessed using the apomorphine-induced stereotypy test, the sucrose preference test, and the delayed spatial alternation task in a T-maze in rats with ventral hippocampus lesions.

Results. Ketamine injection induced significant neurophysiological changes. These included hypersynchronization in the mPFC, evidenced by increased power in the delta, theta, alpha, and gamma frequency ranges (p < 0.05), and desynchronization in the Hipp, indicated by decreased power in the alpha and beta frequency ranges (p < 0.05). Additionally, there was a decrease in functional connectivity between these brain areas (p < 0.05). In contrast to clozapine, compound RU-31 exhibited a normalizing effect on the spectral characteristics of signals and functional connectivity. Behavioral tests showed that both compounds reduced the severity of stereotypy, anhedonia, and cognitive impairment.

Conclusion. The selective 5-HT2A receptor antagonist RU-31 was effective in reversing neurophysiological and behavioral changes associated with schizophrenia-like conditions. Its effect on functional connectivity and cognitive parameters emphasizes the importance of serotonergic modulation in the pathogenesis and treatment of psychotic disorders.

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