Abstract
It is now well established that the glutamatergic system contributes to the pathophysiology of depression. Exposure to stress, a major precipitating factor for depression, enhances glutamate release that can contribute to structural abnormalities observed in the brain of depressed subjects. On the other hand, it has been demonstrated that NMDA antagonists, like ketamine, exert an antidepressant effect at preclinical and clinical levels. On these bases, the purpose of our study was to investigate whether chronic mild stress is associated with specific alterations of the NMDA receptor complex, in adult rats, and to establish whether concomitant antidepressant treatment could normalize such deficits. We found that chronic stress increases the expression of the obligatory GluN1 subunit, as well as of the accessory subunits GluN2A and GluN2B at transcriptional and translational levels, particularly in the ventral hippocampus. Concomitant treatment with the antidepressant duloxetine was able to normalize the increase of glutamatergic receptor subunit expression, and correct the changes in receptor phosphorylation produced by stress exposure. Our data suggest that prolonged stress, a condition that has etiologic relevance for depression, may enhance glutamate activity through post-synaptic mechanisms, by regulating NMDA receptors, and that antidepressants may in part normalize such changes. Our results provide support to the notion that antidepressants may exert their activity in the long-term also via modulation of the glutamatergic synapse.
Highlights
Major depression is a serious, debilitating, life-shortening illness affecting millions of people worldwide, which arises from the complex interaction between susceptibility genes and environmental factors, such as stress [1]
On one hand we want to investigate the effect of chronic mild stress on different component of the glutamatergic system, on the other we examined the impact of chronic antidepressant treatment on the changes produced by prolonged stress exposure
The data emerging from the present work provide novel information with respect to changes of glutamate NMDA receptor subunits as a consequence of exposure to chronic mild stress (CMS), which are to great extent normalized by concomitant treatment with the antidepressant duloxetine
Summary
Major depression is a serious, debilitating, life-shortening illness affecting millions of people worldwide, which arises from the complex interaction between susceptibility genes and environmental factors, such as stress [1]. Available drugs, which have been used for more than 50 years, are based on the increase of biogenic amines at synaptic level While these treatments require 2–4 weeks to produce a clinically meaningful improvement, only 60–65% of patients respond to the initial regimen and, among these, less than half reach remission or become symptom-free [2]. A major obstacle to the development of more effective treatments for major depression has been the limited understanding of its pathophysiology, and of the mechanisms that may be relevant for clinical efficacy. Within this context, dysfunction of the glutamatergic system has emerged as a major pathological feature in depression, and may represent a target for pharmacological intervention [3]. Animals which undergo chronic restraint stress paradigms show an increase in basal, as well as in depolarization-dependent, glutamate release from hippocampal synaptosomes, suggesting a dysregulation in the mechanism responsible for termination of glutamate secretion [9]
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