Brief Treatment With the Glucocorticoid Receptor Antagonist Mifepristone Normalises the Corticosterone-Induced Reduction of Adult Hippocampal Neurogenesis

Swammerdam Institute for Life Sciences, Centre for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
Journal of Neuroendocrinology (Impact Factor: 3.14). 09/2006; 18(8):629-31. DOI: 10.1111/j.1365-2826.2006.01455.x
Source: PubMed


The glucocorticoid receptor antagonist mifepristone has been shown to rapidly and effectively ameliorate symptoms of psychotic major depression. To better understand its mechanism, we investigated mifepristone's cellular effects, and found that it rapidly reversed a chronic corticosterone-induced reduction of adult neurogenesis in rats. Unlike other antidepressants, mifepristone is particularly potent in a high corticosterone environment. These data indicate that similarly to its clinical efficacy, mifepristone's effects on adult neurogenesis are rapid and positive, and may therefore be important for its mechanism of action.

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Available from: Paul J Lucassen
    • "Loi; unpublished observation). Moreover, temporary treatment with MIF in adulthood normalized structural plasticity measures in paradigms associated with prolonged elevation in corticosterone level (Mayer et al., 2006; Oomen et al., 2007; Hu et al., 2012). The outcome of the behavioral experiments was compared with existing literature on various ELS models, where we specifically focused on female rats or mice. "
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    ABSTRACT: We tested the effect of early life stress (ELS) - 24 h maternal deprivation at postnatal day 3 - on cognitive performance and hippocampal structure in 12-17 weeks old female rats. Behavioral performance was examined in: the elevated plus maze, as an index for general anxiety; the rodent Iowa gambling test, probing reward-based decision making; and the object recognition and object-in-location task, to assess non-stressful contextual memory performance. We further determined hippocampal dentate gyrus volume and cell density as well as adult proliferation and neurogenesis rates. Half of the rats was treated with the glucocorticoid receptor antagonist mifepristone during a critical pre-pubertal developmental window (postnatal days 26-28), in an attempt to ameliorate the potentially adverse behavioral consequences of ELS. Neither maternal deprivation nor treatment with the glucocorticoid antagonist affected behavioral performance of the females in any of the tasks. Also, dentate gyrus structure, proliferation and neurogenesis were not different between the groups. The lack of structural differences and a behavioral phenotype in non-stressful hippocampus dependent learning tasks fits with the lack of phenotype generally reported after ELS in female but less so in male rodents. As evident from an extensive literature review, female and male animals appear to respond more similarly to early life adversity when tested in anxiety-related tasks. This agrees with recent findings in humans suggesting that females may be relatively resilient to the structural / hippocampal effects of childhood maltreatment, but not to the anxiety and mood-related psychopathology for which childhood maltreatment is considered a risk factor. Copyright © 2015. Published by Elsevier Ltd.
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    • "Some of them do not integrate into the functional network and thus undergo apoptosis, while others survive (survival). Rodent studies have shown that a large number of factors associated with increased risk of MDD, such as unpredictable stress (Alonso et al., 2004; Mineur et al., 2007), elevated glucocorticoids (Mayer et al., 2006; Wong and Herbert, * Correspondence to: A. Tanti, INSERM U 930, Universite´Franc¸ois Rabelais, Faculte´des Sciences et Techniques, Parc Grandmont, Tours F-37200, France. Tel: +33-2-47-36-70-01. "
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    ABSTRACT: In recent years, both major depression and antidepressant therapy have been linked to adult hippocampal neurogenesis. The hippocampus is not a homogeneous brain area, and a converging body of evidence indicates a functional dissociation along its septo-temporal axis, the dorsal part being involved more in learning/memory and spatial navigation, while the ventral sub-region is linked more to emotional behavior and regulation of the neuroendocrine stress axis. Research has therefore been conducted in an attempt to relate effects of models of depression and of antidepressant therapies to adult neurogenesis along the septo-temporal axis of the hippocampus. The present paper reviews the current literature addressing this question and discusses the possible mechanisms involved and the functional significance of such regional effects. This review shows that animal models of depression elicit an effect restricted to the ventral hippocampus more frequently than a dorsal-specific effect. However, this is also stage specific, and concerns neurogenesis, rather than cell proliferation or survival. Surprisingly, the same does not apply regarding the effects of selective serotonin re-uptake inhibitors that act in a more uniform way on dorsal and ventral adult neurogenesis in most studies. Some recently introduced clinical compounds (e.g., agomelatine) or putative antidepressants have a specific action on the ventral sub-region, indicating that an action restricted to this part of the brain may be sufficient to achieve remission. Finally, non-pharmacological manipulations that are also endowed with antidepressant effects, such as environmental enrichment or physical exercise, also act on both subdivisions, although some studies pointed to specificity of dorsal neurogenesis. The different treatments, acting either on the dorsal or on the ventral sub-regions, could promote recovery by improving either ventral- or dorsal-related functions, both contributing in a different way to treatment efficacy.
    Full-text · Article · Aug 2013 · Neuroscience
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    • "Pretreatment with green tea extract prevented LPS-induced immobility in a dose-dependent manner via COX-2 inhibition [25]. Clinically effective antidepressant medications exert their therapeutic actions partially by modulating HPA function through the regulation of receptor expression, subsequently ameliorating many of the behavioral disturbances associated with depressive-like states [26,27]. A further research is needed to determine the regulatory effect of green tea on glucocorticoids receptors expression and the target genes involved in the reward learning process and the improvement of depressive symptoms. "
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    ABSTRACT: Background Both clinical and preclinical studies revealed that regular intake of green tea reduced the prevalence of depressive symptoms, as well as produced antidepressant-like effects in rodents. Evidence proposed that disturbed reward learning has been associated with the development of anhedonia, a core symptom of depression. However, the relationship between green tea and reward learning is poorly investigated. Our goal was to test whether chronic treatment with green tea in healthy subjects affects the process of reward learning and subsequently regulates the depressive symptoms. Methods Seventy-four healthy subjects participated in a double-blind, randomized placebo-controlled study with oral administration of green tea or placebo for 5weeks. We used the monetary incentive delay task to evaluate the reward learning by measurement of the response to reward trial or no-reward trial. We compared the reaction time of reward responsiveness between green tea and placebo treatment. Furthermore, we selected Montgomery-Asberg depression rating scale (MADRS) and 17-item Hamilton Rating Scale for Depression (HRSD-17) to estimate the depressive symptoms in these two groups. Results The results showed chronic treatment of green tea increased reward learning compared with placebo by decreasing the reaction time in monetary incentive delay task. Moreover, participants treated with green tea showed reduced scores measured in MADRS and HRSD-17 compared with participants treated with placebo. Conclusions Our findings reveal that chronic green tea increased the reward learning and prevented the depressive symptoms. These results also raised the possibility that supplementary administration of green tea might reverse the development of depression through normalization of the reward function.
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