Chronic agomelatine treatment corrects the abnormalities in the circadian rhythm of motor activity and sleep/wake cycle induced by prenatal restraint stress in adult rats

Abstract

Agomelatine is a novel antidepressant acting as an MT1/MT2 melatonin receptor agonist/5-HT2C serotonin receptor antagonist. Because of its peculiar pharmacological profile, this drug caters the potential to correct the abnormalities of circadian rhythms associated with mood disorders, including abnormalities of the sleep/wake cycle. Here, we examined the effect of chronic agomelatine treatment on sleep architecture and circadian rhythms of motor activity using the rat model of prenatal restraint stress (PRS) as a putative 'aetiological' model of depression. PRS was delivered to the mothers during the last 10 d of pregnancy. The adult progeny ('PRS rats') showed a reduced duration of slow wave sleep, an increased duration of rapid eye movement (REM) sleep, an increased number of REM sleep events and an increase in motor activity before the beginning of the dark phase of the light/dark cycle. In addition, adult PRS rats showed an increased expression of the transcript of the primary response gene, c-Fos, in the hippocampus just prior to the beginning of the dark phase. All these changes were reversed by a chronic oral treatment with agomelatine (2000 ppm in the diet). The effect of agomelatine on sleep was largely attenuated by treatment with the MT1/MT2 melatonin receptor antagonist, S22153, which caused PRS-like sleep disturbances on its own. These data provide the first evidence that agomelatine corrects sleep architecture and restores circadian homeostasis in a preclinical model of depression and supports the value of agomelatine as a novel antidepressant that resynchronizes circadian rhythms under pathological conditions.

The Effects of Antidepressant Treatment in Prenatally Stressed Rats Support the Glutamatergic Hypothesis of Stress-Related Disorders

“…We found large reductions in depolarization-evoked glutamate release and in the expression of synaptic vesicle-associated proteins in the ventral hippocampus of adult PRS rats. In these rats, pharmacological enhancement of glutamate release by local injection of a cocktail of GABA B and mGlu2/3 receptor antagonists in the ventral hippocampus was able to reverse anxiety-like behavior (Marrocco et al, 2012). This was the first evidence of a hypofunction of glutamatergic neurotransmission in the ventral hippocampus in a model of depres-sion and anxiety, which has predictive, face, and construct validity.…”

“…A growing body of evidence suggests that abnormalities in hippocampal glutamatergic transmission are involved in the pathophysiology of mood and anxiety disorders (Tordera et al, 2007;Ongür et al, 2008;Garcia-Garcia et al, 2009;Chen et al, 2010;.…”

“…We were able to demonstrate a direct relationship between hippocampal glutamate release and anxiety in rats subjected to prenatal restraint stress (PRS; Marrocco et al, 2012). PRS rats (i.e., the offspring of mothers exposed to repeated episodes of restraint stress during the last 10 d of pregnancy) are characterized by a prolonged corticosterone response to acute stress, and by neurochemical and behavioral abnormalities that are typically linked to depression and anxiety (Dugovic et al, 1999;Darnaudéry and Maccari, 2008;Zuena et al, 2008;Mairesse et al, 2013).…”

“…PRS rats (i.e., the offspring of mothers exposed to repeated episodes of restraint stress during the last 10 d of pregnancy) are characterized by a prolonged corticosterone response to acute stress, and by neurochemical and behavioral abnormalities that are typically linked to depression and anxiety (Dugovic et al, 1999;Darnaudéry and Maccari, 2008;Zuena et al, 2008;Mairesse et al, 2013). We found large reductions in depolarization-evoked glutamate release and in the expression of synaptic vesicle-associated proteins in the ventral hippocampus of adult PRS rats.…”

“…We examined the glutamatergic synapse by measuring K ϩ -evoked glutamate release from superfused synaptosomes and by analyzing the synaptic expression of vesicle-associated membrane protein (VAMP) as a representative protein of the SNARE complex, and of proteins regulating the trafficking of synaptic vesicles, such as synapsins, munc-18, and Rab3A (see also Marrocco et al, 2012). We report that chronic systemic treatment with either fluoxetine or agomelatine corrects the glutamatergic hypofunction in the ventral hippocampus and the associated behavioral abnormalities in adult PRS rats.…”