Boldizsár Czéh, October 2, 2001, 10.1073 /pnas.211427898
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. 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).
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.
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.

Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus
Lemaire,Koehl, Le Moal & Abrous Bordeaux II
Early experiences such as prenatal stress significantly influence the development of the brain and the organization of behavior. In particular, prenatal stress impairs memory processes but the mechanism for this effect is not known. Hippocampal granule neurons are generated throughout life and are involved in hippocampal-dependent learning. Here, we report that prenatal stress in rats induced lifespan reduction of neurogenesis in the dentate gyrus and produced impairment in hippocampal-related spatial tasks. Prenatal stress blocked the increase of learning-induced neurogenesis. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for psychopathological vulnerabilities in aging.
Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increased glucocorticoid reactivity to stress

Magariños and McEwen The Rockefeller University
Chronic stressor that produces retraction and simplification of apical dendrites of hippocampal pyramidal neurons. Diabetes also induces morphological changes in the presynaptic mossy fiber terminals that form excitatory synaptic contacts with the proximal apical dendrites. One effect, synaptic vesicle depletion, occurs in diabetes as well as after repeated stress and Cort treatment. However, diabetes produced other MFT structural changes that differ qualitatively and quantitatively from other treatments. Furthermore, whereas 7 d of repeated stress was insufficient to produce dendritic or synaptic remodeling in nondiabetic rats, it potentiated both dendritic atrophy and MFT synaptic vesicle depletion in STZ rats. These changes occurred in concert with adrenal hypertrophy and elevated basal Cort release as well as hypersensitivity and defective shutoff of Cort secretion after stress. Thus, as an endogenous stressor, STZ diabetes not only accelerates the effects of exogenous stress to alter hippocampal morphology; it also produces structural changes that overlap only partially with those produced by stress and Cort in the nondiabetic state.

Limbic-hypothalamic-pituitary-adrenal axis in depression: literature review
Twardowska K; Rybakowski J
Kliniki Psychiatrii Dorosych w Poznaniu. Psychiatr Pol, 1996 Sep, 30:5, 741-55

Increased cortisol concentration has until now been the best documented biochemical abnormality in depression. Pathological results of the Dexamethasone Suppression Test pointing to hyperactivity of LHPA axis are found in about half of depressive patients. According to most recent research, primary disturbance of LHPA axis concerns hypothalamus and limbic system. An association was found between disturbances of LHPA axis in depression and immune system abnormalities in this illness. Disturbances of serotonergic and noradrenergic neurotransmission in depression may also partially result from LHPA axis dysfunction. Influencing LHPA axis may underlie the mechanism of new antidepressant drug, tianeptine. Recently, it was found that classical tricyclic antidepressant drugs as well as electroconvulsive may also act on LHPA in regulatory way.

Watanabe Y, Gould E, Daniels DC, Cameron H, McEwen BS.
Laboratory of Neuroendocrinology, Rockefeller University, New York, NY 10021.

Repeated 6-h daily restraint stress over 21 days reduces length and number of branch points of hippocampal CA3c pyramidal dendrites in the hippocampal formation of adult male rats. This effect is mimicked by daily injections of 40 mg/kg corticosterone. Daily treatment with tianeptine (15 mg/kg) prior to stress sessions or the corticosterone treatment prevented these effects of stress or corticosterone, respectively. Tianeptine treatment did not prevent the effects of stress to increase adrenal/body weight ratio, nor did it prevent the effects of stress to decrease body weight gain, indicating that its actions are not mediated solely by effects on stress-induced secretion of corticosterone. Because tianeptine is known to enhance neural uptake of serotonin, these results suggest that the serotonergic system may be involved in modulating stress and corticosterone effects on dendritic morphology.

Delbende C, Contesse V, Mocaer E, Kamoun A, Vaudry H.
European Institute for Peptide Research, CNRS URA 650.

The possible effect of tianeptine, a novel antidepressant agent, on the neuroendocrine response to stress was investigated in adult male rats. Tube restraint stress for 30 min induced a marked increase of plasma ACTH and corticosterone. A single i.p. injection of tianeptine (10 mg/kg), 120 min before stress caused a significant decrease of ACTH and corticosterone levels. In order to investigate the kinetics of the effect of tianeptine, the drug was injected at various times (from 15 min to 12 h) before restraint stress. The inhibitory effect of tianeptine on stress-induced elevations of plasma ACTH and corticosterone occurred from 1 to 3 h after the injection. Administration of increasing doses of tianeptine revealed that only the highest doses (10 and 20 mg/kg) had a significant effect on stress-evoked stimulation of ACTH and corticosterone secretion. These results show that the antidepressant, tianeptine, reduces the activation of the hypothalamo-pituitary-adrenal (HPA) axis induced by restraint stress. Since depressed patients generally exhibit an elevated cortisol level, the present data suggest that part of the therapeutic properties of tianeptine could be accounted for by the effect of this antidepressant to modulate the activity of the HPA axis.
Stress facilitates classical conditioning in males, but impairs classical conditioning in females through ovarian hormones
Gwendolyn E. Wood and Tracey J. Shors Princeton University
Exposure to restraint and brief intermittent tailshocks facilitates associative learning of the classical conditioned eyeblink response in male rats. Based on evidence of sex differences in learning and responses to stressful events, we investigated sexually dimorphic effects of a stressor of restraint and intermittent tailshock on classical eyeblink conditioning 24 h after stressor cessation. Our results indicate that exposure to the acute stressor had diametrically opposed effects on the rate of acquisition of the conditioned response in male vs. female rats. Exposure to the stressor facilitated acquisition of the conditioned response in males, whereas exposure to the same stressful event dramatically impaired acquisition in females. We further demonstrate that the stress-induced impairment in female conditioning is dependent on the presence of ovarian hormones. Conditioning of stressed sham-ovariectomized females was significantly impaired relative to the unstressed controls, whereas conditioning in stressed ovariectomized females was not impaired. We present additional evidence that estrogen mediates the stress-induced impairment in female acquisition. Females administered sesame oil vehicle and then stressed were significantly impaired relative to their unstressed controls, whereas females administered the estrogen antagonist tamoxifen prior to stress were not impaired. In summary, these results indicate that exposure to the same aversive event can induce opposite behavioral responses in males vs. females. These effects underscore sex differences in associative learning and emotional responding, and implicate estrogen in the underlying neuronal mechanism

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> Estrés y Trastornos Adaptativos
> Diagnósticos DSM y ICD 10
> Farmacología: Tianeptin

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