Chronic clomipramine treatment increases hippocampal volume in rats exposed to chronic unpredictable mild stress

Abstract

It is well known that neuroinflammation is closely related to the pathophysiology of depression. Due to individual differences in clinical research, the reduction of hippocampal volume in patients with depression is still controversial. In this experiment, we studied a typical kind of tricyclic antidepressant, clomipramine. We designed a series of experiments to find its role in depressive-like behavior, hippocampal neuroinflammation as well as hippocampal volume changes induced by chronic unpredictable mild stress (CMS). Rats exhibited defective behavior and hippocampal neuroinflammation after 12 weeks of CMS, which included elevated expression of cleaved interleukin-1β (IL-1β) and NLRP3 inflammasome together with the activation of microglia. Rats exposed to CMS showed weakened behavioral defects, reduced expression of IL-18, IL-6, and IL-1β along with reversed activation of microglia after clomipramine treatment. This indicates that the antidepressant effect of clomipramine may be related to the reduced expression of NLRP3 inflammasome and cleaved IL-1β. Moreover, we found an increased hippocampal volume in rats exposed to CMS after clomipramine treatment while CMS failed to affect hippocampal volume. All these results indicate that the NLRP3 inflammasome of microglia in the hippocampus is related to the antidepressant effects of clomipramine and CMS-induced depressive-like behavior in rats.

Dulaglutide treatment reverses depression‐like behavior and hippocampal metabolomic homeostasis in mice exposed to chronic mild stress

“…A video tracking system (SMART 3.0, Spain) was used to videotape the total activity of the mice for 5 min, during which time the mice were allowed to move freely. The data on the time spent in the central area and the total distance traveled were collected from the video (Zhang et al., 2022 ).…”

“…A combination of genetic, neurological, and psychological factors contribute to the overall risk of depression (Zhang et al., 2022 ). A family history of depression, early life neglect and abuse, life stress, and comorbid physical illnesses all increase the risk of depression (Beurel E et al., 2020 ).…”

“…As a result, it is broadly used to study the role of stress in the etiology of depression (Duan et al., 2022 ; Faria et al., 2014 ; Willner P., 2017 ). The hippocampus is a complex brain region involved in depression that exhibits morphological and functional alterations in response to stress (Zhang et al., 2022 ). Neuropathological findings have suggested a decrease in neuronal and glial size, loss of dendrites, reduced expression of synaptic markers, decreased neurogenesis, and an increase in apoptosis in the hippocampus of animal models of depression (Zhang et al., 2018 ; Zhang et al., 2022 ).…”

Roles of microglia in adult hippocampal neurogenesis in depression and their therapeutics

“…In another study, Zhang et al. found that clomipramine modulated the microglial NLRP3 inflammasome to reduce depressive behavior and increase hippocampal volume in exposure to CUMS model of rats ( 204 ). Meanwhile, amitriptyline was found to inhibit LPS-induced microglial expression of pro-inflammatory factors ( 205 ) and increase BDNF expression in microglia ( 206 ).…”

“…Currently, SSRIs are the first line of antidepressants used in clinical practice. This category includes sertraline, paroxetine, fluvoxamine, fluoxetine, citalopram, and escitalopram, which selectively inhibit 5-HT reuptake by antagonistically binding presynaptic membrane 5-HT transporters in neurons, thus increasing the concentration of 5-HT in the synaptic cleft ( 204 , 210 ). Previous studies have shown that adult neurogenesis and olfactory memory are positively regulated by fluoxetine.…”