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 mg/kg). 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.

Figure 1

Proton magnetic resonance spectroscopy showing the effect of long term psychosocial stress and concomitant tianeptine application on functional brain neurochemistry (mean spectra for three experimental groups; n = 6 animals per group): Control (A), Stress (B), Stress + Tianeptine (C). The spectra (STEAM, TR/TE/TM = 6000/20/10 ms, 0.245 ml volume of interest, 64 accumulations per animal) include resonances from N-acetyl-aspartate (NAA), creatine and phosphocreatine (Cr), choline-containing compounds (Cho), and myo-inositol (Ins). Individual spectra were scaled in proportion to the brain water concentration before averaging across animals. Arrows indicate statistically significant differences in comparison with animals from the Control group. Note that the decreases of Cho, Cr, and NAA in the Stress group are prevented in the Stress + Tianeptine group.

Figure 2

Cell proliferation in the hippocampal dentate gyrus of the tree shrew was quantified with the use of BrdUrd immunohistochemistry. (A) A representative photomicrographs of a Control animal. The majority of proliferating cells was found dominantly in the subgranular zone defined as a two-cell-body-wide zone between the granule cell layer (gcl) and hilus (h). Positively labeled cells generally occurred singly or in small clusters comprised of three to five cells. Scale bar = 100 μm. (B) Chronic psychosocial stress significantly suppressed cell proliferation in the hippocampal dentate gyrus (Stress), whereas chronic tianeptine treatment reversed the stress-induced effect (Stress + Tianeptine). Antidepressant treatment alone had an insignificant effect on hippocampal cell proliferation (Control + Tianeptine). Results are given as mean ± SEM number of BrdUrd-positive cells in the hippocampal dentate gyrus. *, P < 0.05 vs. Controls.

Figure 3

Postmortem volumetry of the hippocampus. Chronic psychosocial stress resulted in a decrease (7%) of the hippocampal volume compared with unstressed controls (P = 0.40). This decrease was prevented by tianeptine treatment (Stress + Tianeptine vs. Stress; *, P < 0.05).