Modulatory Effect of Serotonergic System in Pentylenetetrazole-Induced Seizures and Associated Memory Deficit: Role of 5-HT1A and 5-HT2A/2C

Abstract

Background and purpose: Recent studies have recognised the memory deficit as one of the most common psychiatric issues in the patients with epilepsy, which severely affects the quality of life. Our previous studies have demonstrated the possible involvement of serotonergic system in the pathogenesis of epilepsy and associated memory deficit. The possible involvement of 5-HT_1A and 5-HT_2A/2C receptor has not been explored yet. Therefore, this study has been envisaged to explore the effect of 5-HT_1A and 5-HT_2A/2C receptor modulation on epilepsy and memory deficit in pentylenetetrazole-kindled mice.

Methods: In the present experimental approach, we examined the efficacy of modulation of 5-HT_1A and 5-HT_2A/2C receptor in pentylenetetrazole-induced kindling in male Swiss mice (n=75). Mice were kindled by sub-convulsive dose of pentylenetetrazole (35 mg/kg, intraperitoneal injection), at the interval of 48±2 hours). Successfully kindled animals were treated with 5-HT_1A and 5-HT_2A/2C receptor modulators. The effect of different treatments on seizure severity score and memory impairment was analysed.

Results: 5-HT_1A receptor agonist improved the memory functions while seizure severity was not improved, and the opposite effect was observed with 5-HT_1A receptor antagonist. On the other hand, 5-HT_2A/2C receptor agonist significantly improved memory deficit as well as seizure severity in the kindled animals.

Conclusions: The outcome of the study indicates the possible involvement of 5-HT_2A/2C receptor in the pathogenesis of epilepsy and associated memory deficit, which can be further explored for its management.

Keywords: Comorbidity; Epilepsy; Kindling; Memory disorders; Pentylenetetrazole; Receptor; Serotonin.

Figure 1

Schematic representation of experimental protocol. PTZ, pentylenetetrazole; 8-OH-DPAT, 5-HT_1A receptor agonists; WAY100,635, 5-HT_1A receptor antagonists; R (-) DOI, 5-HT_2A receptor agonist; Olanzapine, 5-HT_2A/2C receptor antagonist.

Figure 2

Effect of different treatments on behaviour of mice. On day 20 the behaviour of animal was recorded and effect of different treatments was recorded. (A) Effect on seizure severity score, (B) effect on transfer latency in elevated plus maze, (C) effect on number of mistakes in passive shock avoidance paradigm, and (D) effect on step down latency in passive shock avoidance paradigm. Each value is expressed as mean±standard error of means. The significance level was considered at p<0.05 (one way ANOVA followed by Tukey’s test). 8-OH-DPAT, 5-HT_1A receptor agonists; WAY100,635, 5-HT_1A receptor antagonists; R (-) DOI, 5-HT_2A receptor agonist; Olanzapine, 5-HT_2A/2C receptor antagonist. *As compared to naïve. ^†As compared to vehicle treated group.