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      The neurobiological properties of Tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation

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          Abstract

          Tianeptine is a clinically used antidepressant that has drawn much attention, because this compound challenges traditional monoaminergic hypotheses of depression. It is now acknowledged that the antidepressant actions of tianeptine, together with its remarkable clinical tolerance, can be attributed to its particular neurobiological properties. The involvement of glutamate in the mechanism of action of the antidepressant tianeptine is consistent with a well-developed preclinical literature demonstrating the key role of glutamate in the mechanism of altered neuroplasticity that underlies the symptoms of depression. This article reviews the latest evidence on tianeptine’s mechanism of action with a focus on the glutamatergic system which could provide a key pathway for its antidepressant action. Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, and therefore offer new insights into how tianeptine may be useful in the treatment of depressive disorders.

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          Most cited references122

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          A neurotrophic model for stress-related mood disorders.

          There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neurotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been observed in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a critical examination of the neurotrophic hypothesis of depression that has evolved from this work, including analysis of preclinical cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.
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            Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.

            Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action. The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine's behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput. Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors. NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.
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              Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons.

              The hippocampus and the amygdala are essential components of the neural circuitry mediating stress responses. The hippocampus, which provides negative feedback regulation of the stress response, is particularly vulnerable to degenerative changes caused by chronic stress. Unlike the hippocampus, relatively little is known about how stress affects the amygdala and the nature of its role in the stress response. Hence, we examined the effects of two different models of chronic stress on hippocampal and amygdaloid neuronal morphology in rats. In agreement with previous reports, chronic immobilization stress (CIS) induced dendritic atrophy and debranching in CA3 pyramidal neurons of the hippocampus. In striking contrast, pyramidal and stellate neurons in the basolateral complex of the amygdala exhibited enhanced dendritic arborization in response to the same CIS. Chronic unpredictable stress (CUS), however, had little effect on CA3 pyramidal neurons and induced atrophy only in BLA bipolar neurons. These results indicate that chronic stress can cause contrasting patterns of dendritic remodeling in neurons of the amygdala and hippocampus. Moreover, CIS, but not CUS, reduced open-arm activity in the elevated plus-maze. These findings raise the possibility that certain forms of chronic stress, by affecting specific neuronal elements in the amygdala, may lead to behavioral manifestations of enhanced emotionality. Thus, stress-induced structural plasticity in amygdala neurons may provide a candidate cellular substrate for affective disorders triggered by chronic stress.
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                Author and article information

                Contributors
                Journal
                9607835
                20545
                Mol Psychiatry
                Mol. Psychiatry
                Molecular psychiatry
                1359-4184
                1476-5578
                28 May 2010
                25 August 2009
                March 2010
                01 September 2010
                : 15
                : 3
                : 237-249
                Affiliations
                Alfred E. Mirsky Professor Head, Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology. The Rockefeller University 1230 York Avenue New York, NY 10021, USA, Phone: +1 212 327 8624
                National Center for Biological Sciences, Bangladore 560065, India, Phone: +91 80 23636421
                Medical Research Division, Veterans Hospital, 13000 Bruce B. Downs Blvd., Tampa, FL, 33612;Center for Preclinical and Clinical Research on PTSD; Departments of Psychology and Molecular Pharmacology and Physiology, University of South Florida, 4202 E. Fowler Ave., PCD 4118G, Tampa, FL, 33620, USA, Phone: +1 813974048
                INSERM, Physiopathologie des Maladies Psychiatriques, U894 and Université Paris Descartes, Faculté de Médecine Paris Descartes, Paris, France, Phone: +33 1 40788631
                Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, Phone: 803 733-3237
                Center for Molecular Medicine, Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden, Phone: +46 (8) 52 48 79 26
                Clinical Neurobiology Laboratory, German Primate Center, Department of Neurology and DFG Research Center Molecular Physiology of the Brain (CMPB), University of Göttingen, 37077 Göttingen, Germany, Phone: +49-551-3851 130
                Article
                NIHMS201077
                10.1038/mp.2009.80
                2902200
                19704408
                9e950964-c17c-4d5d-a19c-42e50647aef0
                History
                Funding
                Funded by: National Institute of Mental Health : NIMH
                Award ID: R01 MH041256-23 || MH
                Categories
                Article

                Molecular medicine
                tianeptine,hippocampus,amygdala,stress,antidepressant
                Molecular medicine
                tianeptine, hippocampus, amygdala, stress, antidepressant

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