A biopotential-mediated approach to studying the effects of a benzimidazole derivative with 5-HT2A antagonist activity and evaluating its antipsychotic effects in the neonatal ventral hippocampal lesion model in rats

Abstract

Introduction. In recent years, the role of the serotonergic system in the pathogenesis of schizophrenia has been extensively studied with a particular focus on 5-HT2A receptors as pharmacological targets. The aim of the study was to evaluate the antipsychotic activity of the novel benzimidazole derivative, RU-31, with a 5-HT2A antagonist activity by analysis of brain bioelectrical activity and behavioral tests in a rat model of psychosis induced by neonatal ventral hippocampal lesions. Methods. Rats (250-290 g) were implanted with electrodes to record the bioelectrical activity of the brain. Data were processed using a convolutional autoencoder, and the UMAP algorithm, and distances between signal clusters in the parametric space were calculated. Changes in the brain activity after the administration of RU-31 were compared with reference drugs (chlorpromazine, haloperidol, clozapine, risperidone, quetiapine, amitriptyline, fluoxetine, paroxetine, escitalopram, ketanserin, cyproheptadine, hydroxyzine, sumatriptan, ondansetron, atropine, suprastin). Psychosis was modeled in rats by bilateral injection of ibotenic acid (1.5 μg) into the ventral hippocampus on postnatal day 7. The following groups were formed: control (saline 10 ml/kg); RU-31 (10 mg/kg); clozapine (7,5 mg/kg), and sham-operated animals. The groups were then evaluated using the open field test, social interaction test, and novel object recognition test. Results. Analysis of the brain bioelectrical activity showed that RU-31 had a high degree of similarity to both clozapine (similarity coefficient 0.764) and ketanserin (similarity coefficient 0.756). In the open field test, rats with ibotenic acid-induced lesions displayed hyperlocomotion (Me = 98 crossings, IQR = 50, p<0.01). Administration of RU-31 significantly reduced hyperlocomotion (Me = 58, IQR = 38.75, p<0.05), with a comparable effect observed for clozapine (Me = 47, IQR = 40, p < 0.01). In the social interaction test, RU-31 significantly increased the active behavior duration (Me = 227.6 s, IQR = 59.5, p<0.05), whereas clozapine did not induce a statistically significant effect (Me = 152.8, IQR = 91.4, p>0.05). In the novel object recognition test, RU-31 and clozapine enhanced the discrimination index in the long-term retention phase (Me=0.73, IQR=0.34, and Me=0.68, IQR=0.32, p<0.05, respectively). Conclusion. The findings confirm the antipsychotic potential of RU-31, particularly in addressing negative and cognitive symptoms, suggesting its promise as a candidate for treating refractory psychotic disorders.