The antidepressant agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats

Abstract

Agomelatine, a novel antidepressant with established clinical efficacy, acts as a melatonin receptor agonist and 5-HT(2C) receptor antagonist. As stress is a significant risk factor in the development of depression, we sought to determine if chronic agomelatine treatment would block the stress-induced impairment of memory in rats trained in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. Moreover, since neural cell adhesion molecule (NCAM) is known to be critically involved in memory consolidation and synaptic plasticity, we evaluated the effects of agomelatine on NCAM, and polysialylated NCAM (PSA-NCAM) expression in rats given spatial memory training with or without predator stress. Adult male rats were pre-treated with agomelatine (10 mg/kg i.p., daily for 22 d), followed by a single day of RAWM training and memory testing. Rats were given 12 training trials and then they were placed either in their home cages (no stress) or near a cat (predator stress). Thirty minutes later the rats were given a memory test trial followed immediately by brain extraction. We found that: (1) agomelatine blocked the predator stress-induced impairment of spatial memory; (2) agomelatine-treated stressed, as well as non-stressed, rats exhibited a rapid training-induced increase in the expression of synaptic NCAM in the ventral hippocampus; and (3) agomelatine treatment blocked the water-maze training-induced decrease in PSA-NCAM levels in both stressed and non-stressed animals. This work provides novel observations which indicate that agomelatine blocks the adverse effects of stress on hippocampus-dependent memory and activates molecular mechanisms of memory storage in response to a learning experience.

Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling

“…A number of studies have supported the involvement of additional mechanisms in the detrimental effects of stress on hippocampal structure and function (68,77), including activation of glutamate (43,45,49,63), serotonin (27,37,42,47), and GABA (78) receptors. The resulting downstream processes might be reversed by antidepressants including lithium (55,79), tianeptine, and agomelatine (28,63), potentially via cellular cascades including neural cell adhesion molecules (47,79).…”

“…The resulting downstream processes might be reversed by antidepressants including lithium (55,79), tianeptine, and agomelatine (28,63), potentially via cellular cascades including neural cell adhesion molecules (47,79).…”

“…A large body of work has demonstrated that chronic stress may result in memory deficits (26)(27)(28)(29)(30)(31) and abnormal LTP (32)(33)(34), and these functional deficits often are accompanied by diminished dendritic arborization (35)(36)(37)(38)(39)(40)(41)(42). Short-term or acute stress, lasting minutes to hours, also has been found to affect memory (43)(44)(45)(46)(47). In parallel, short-term stress has been reported to influence LTP (48)(49)(50)(51)(52) and reduce the density of dendritic spines in area CA1 (44,53) or area CA3 (51,54).…”

A Study on the Effects of Agomelatine on Food Intake and Body Weight in Restraint Stress Model in Adult Swiss Albino Mice

“…It has been found to be an effective antidepressant and an anxiolytic [6]. Agomelatine synchronizes the circadian rhythm and also ameliorates stress-related changes like depressive symptoms by modulating the cytoskeleton micro tubular dynamics and synaptic markers such as brain derived neurotrophic factor in amygdala and hippocampus [13,14]. Agomelatine antagonizes serotonin 2C receptor which is an important mediator of satiety [15].…”

Antidepresan İlaçların Öğrenme ve Bellek Mekanizmasına Etkileri

“…Conboy ve ark. 22 gün süre ile agomelatinin 10 mg/kg dozunda intraperitoneal olarak vermişler ve sıçan hipokampusunda nöronal hücre adezyon molekülünün (NCAM) ekspresyonunu artırdığını ve stresle indüklenen uzaysal bellek bozulmalarını düzelttiğini göstermişler 86 . Yakın tarihlerde gerçekleştirilen ve 2.5-40 mg/kg'lık doz aralığında verilen agomelatinin sıçanlarda "yeni obje tanıma testi" ile değerlendirilen bellek parametrelerinde olumlu değişiklikler yaptığı rapor edilmiştir 87 .…”