Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine

Abstract

Stress-induced structural remodeling in the adult hippocampus, involving debranching and shortening of dendrites and suppression of neurogenesis, provides a cellular basis for understanding the impairment of neural plasticity in the human hippocampus in depressive illness. Accordingly, reversal of structural remodeling may be a desirable goal for antidepressant therapy. The present study investigated the effect of tianeptine, a modified tricyclic antidepressant, in the chronic psychosocial stress model of adult male tree shrews (Tupaia belangeri), a model with high validity for research on the pathophysiology of major depression. Animals were subjected to a 7-day period of psychosocial stress to elicit stress-induced endocrine and central nervous alterations before the onset of daily oral administration of tianeptine (50 mg͞kg). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy, cell proliferation in the dentate gyrus was quantified by using BrdUrd immunohistochemistry, and hippocampal volume was measured post mortem. Chronic psychosocial stress significantly decreased in vivo concentrations of N-acetyl-aspartate (؊13%), creatine and phosphocreatine (؊15%), and choline-containing compounds (؊13%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (؊33%). These stress effects were prevented by the simultaneous administration of tianeptine yielding normal values. In stressed animals treated with tianeptine, hippocampal volume increased above the small decrease produced by stress alone. These findings provide a cellular and neurochemical basis for evaluating antidepressant treatments with regard to possible reversal of structural changes in brain that have been reported in depressive disorders.neurogenesis ͉ proton magnetic resonance spectroscopy ͉ depression ͉ hippocampus ͉ tree shrew D epressive disorders are among the most common and lifethreatening illnesses and represent a significant public health problem (1). Despite extensive preclinical and clinical investigations, the exact neurobiological processes leading to depression and the mechanisms responsible for the therapeutic effects of antidepressant drugs are not completely understood (2).The hippocampus is one of the brain structures that has been extensively studied with regard to the actions of stress, depression and antidepressant actions (3, 4). Recent imaging studies in humans revealed that the hippocampus undergoes selective volume reduction in stress-related neuropsychiatric disorders such as recurrent depressive illness (5-7). Within the hippocampal formation, the dentate gyrus is one of the few brain structures where production of new neurons occurs even in the adult mammalian brain (8-10). Several experiential, neuroendocrine, and genetic factors that regulate neurogenesis in the adult dentate gyrus have been identified (11). One factor that potently suppresses adult granule cell prolife...

Chronic Social Stress Inhibits Cell Proliferation in the Adult Medial Prefrontal Cortex: Hemispheric Asymmetry and Reversal by Fluoxetine Treatment

“…The modified unbiased stereology protocol (Keuker et al, 2001) we used has been successful in quantifying BrdU labeling (Malberg et al, 2000;Czéh et al, 2001). Every sixth section throughout the dentate gyrus was examined, yielding a mean of 16 sections per animal.…”

Maintenance Treatment with Fluoxetine is Necessary to Sustain Normal Levels of Synaptic Markers in an Experimental Model of Depression: Correlation with Behavioral Response

“…On the contrary, the effect of antidepressant treatment on cytoskeletal and synaptic plasticity remains controversial. For instance, despite Czéh et al (2001) have shown that the atypical antidepressant tianeptine prevents the hippocampal volume loss induced by stress and Magariños et al (1999) have proved tianeptine efficacy to reverse stress-induced rat hippocampal atrophy visualized by Golgi staining, fluoxetine (FLX) has not been effective on these cytoskeletal changes (Magariños et al, 1999). In coincidence with these preclinical reports, clinical studies have not been able to confirm that antidepressant treatment reverses the hippocampal volume diminution found in depressed patients (Neumeister et al, 2005).…”

Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine

“…In line with the antiapoptotic effect observed post-mortem by Lucassen et al, 85 tianeptine prevented the stressinduced reduction of the in vivo brain metabolite levels of N-acetylaspartate. 22 Several other studies have shown protective effects of antidepressants in different models, and mostly in the hippocampus. 58,86 In a maternal deprivation and a prenatal restraint stress model, alterations in granule cell number and neurogenesis as well as apoptosis occur 87,88 and these changes could be normalized by fluoxetine treatment.…”

“…54 Tianeptine's effects of preventing or even, to some extent, reversing stress-induced structural plasticity have also been demonstrated in a more naturalistic psychosocial stress model. Czéh et al 22 have investigated whether administration of tianeptine would oppose stress-induced adverse effects in the hippocampal formation in the chronic psychosocial stress model of adult male tree shrews (Tupaia belangeri). This animal model has a high validity to investigate the pathophysiology of depressive disorders.…”

“…10,20 Neurogenesis in the dentate gyrus of the hippocampal formation may be involved in the mechanism of action of a wide range of antidepressants. [21][22][23] This fascinating finding requires further research in order to understand how the mechanism of antidepressant treatments might converge to regulate common events such as neurogenesis and other forms of structural plasticity. Moreover, the concept of a serotonergic deficit in depression is particularly challenged by the drug tianeptine (S-1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt), an antidepressant with structural similarities to the tricyclic antidepressant agents but with different pharmacological properties.…”