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

Feb 8, 2012The international journal of neuropsychopharmacology

Long-term agomelatine treatment improves daily activity and sleep problems caused by prenatal stress in adult rats

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Abstract

Chronic treatment with agomelatine (2000 ppm in the diet) reversed sleep architecture changes in a rat model of depression.

Adult rats exposed to prenatal restraint stress exhibited reduced slow wave sleep and increased rapid eye movement (REM) sleep.
PRS rats showed an increase in both the number of REM sleep events and motor activity before the dark phase of the light/dark cycle.
An increase in c-Fos gene expression was observed in the hippocampus of adult PRS rats prior to the dark phase.
Agomelatine treatment corrected the observed sleep and circadian rhythm disturbances in PRS rats.
The effects of agomelatine on sleep were diminished by the MT1/MT2 melatonin receptor antagonist, S22153, which induced similar sleep disturbances.

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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.

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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

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