Widespread hypothalamic-pituitary-adrenocortical axis-relevant and mood-relevant effects of chronic fluoxetine treatment on glucocorticoid receptor gene expression in mice.
ABSTRACT Tricyclic antidepressants (TCAs) have been used to treat melancholic depression, which has been associated with elevated hypothalamic-pituitary-adrenocortical (HPA) axis activity, whereas patients suffering from atypical depression, which is often associated with decreased HPA axis activity, show preferential responsiveness to monoamine oxidase inhibitors (MAOIs). We previously reported drug-specific effects of the TCA imipramine and the MAOI phenelzine on HPA axis-relevant endpoints in mice that may explain differential antidepressant responses in melancholic vs. atypical depression. However, selective serotonin reuptake inhibitors (SSRIs) are reported to be effective in both melancholic and atypical depression. We therefore hypothesized that SSRIs would share HPA axis-related effects with either TCAs or MAOIs. To test this hypothesis, we measured HPA axis-relevant gene expression in male C57BL/6 mice treated for 5 weeks with 10 mg/kg/day fluoxetine. To control for potential fluoxetine-induced changes in glucocorticoid secretion, mice were adrenalectomized and given fixed levels of glucocorticoids. Fluoxetine decreased glucocorticoid receptor (GR) gene expression in the prefrontal cortex, amygdala, locus coeruleus and dorsal raphé nucleus, and increased locus coeruleus tyrosine hydroxylase and dorsal raphé nucleus tryptophan hydroxylase-2 (TPH2) gene expression. These results resembled those that we previously reported for MAOI treatment, but included decreases in GR and increases in TPH2 gene expression in the dorsal raphé nucleus that were induced by TCAs but not MAOIs. Correlating with inhibitory effects on central amygdala GR gene expression, fluoxetine also decreased amygdala corticotropin-releasing hormone gene expression, an effect not previously observed with MAOIs or TCAs. These actions may be relevant to the efficacy of SSRIs in treating a range of depression and anxiety disorders.
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ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs) are among the most widely prescribed drugs in psychiatry. Based on the fact that SSRIs increase extracellular monoamine levels in the brain, the monoamine hypothesis of depression was introduced, postulating that depression is associated with too low serotonin, dopamine and noradrenaline levels. However, several lines of evidence indicate that this hypothesis is too simplistic and that depression and the efficacy of SSRIs are dependent on neuroplastic changes mediated by changes in gene expression. Because a coherent view on global gene expression is lacking, we aim to provide an overview of the effects of SSRI treatment on the final targets of 5-HT receptor signal transduction pathways, namely the transcriptional regulation of genes. We address gene polymorphisms in humans that affect SSRI efficacy, as well as in vitro studies employing human-derived cells. We also discuss the molecular targets affected by SSRIs in animal models, both in vivo and in vitro. We conclude that serotonin transporter gene variation in humans affects the efficacy and side-effects of SSRIs, whereas SSRIs generally do not affect serotonin transporter gene expression in animals. Instead, SSRIs alter mRNA levels of genes encoding serotonin receptors, components of non-serotonergic neurotransmitter systems, neurotrophic factors, hypothalamic hormones and inflammatory factors. So far little is known about the epigenetic and age-dependent molecular effects of SSRIs, which might give more insights in the working mechanism(s) of SSRIs.Pharmacology [?] Therapeutics 08/2012; 136(3). DOI:10.1016/j.pharmthera.2012.08.015 · 7.75 Impact Factor
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ABSTRACT: This paper highlights a symposium on stress risk factors and stress susceptibility, presented at the Neurobiology of Stress workshop in Boulder, CO, in June 2010. This symposium addressed factors linking stress plasticity and reactivity to stress pathology in animal models and in humans. Dr. J. Radley discussed studies demonstrating prefrontal cortical neuroplasticity and prefrontal control of hypothalamo-pituitary-adrenocortical axis function in rats, highlighting the emerging evidence of the critical role that this region plays in normal and pathological stress integration. Dr. M. Kabbaj summarized his studies of possible epigenetic mechanisms underlying behavioral differences in rat populations bred for differential stress reactivity. Dr. L. Jacobson described studies using a mouse model to explore the diverse actions of antidepressants in brain, suggesting mechanisms whereby antidepressants may be differentially effective in treating specific depression endophenotypes. Dr. R. Yehuda discussed the role of glucocorticoids in post-traumatic stress disorder (PTSD), indicating that low cortisol level may be a trait that predisposes the individual to development of the disorder. Furthermore, she presented evidence indicating that traumatic events can have transgenerational impact on cortisol reactivity and development of PTSD symptoms. Together, the symposium highlighted emerging themes regarding the role of brain reorganization, individual differences, and epigenetics in determining stress plasticity and pathology.Stress (Amsterdam, Netherlands) 09/2011; 14(5):481-97. DOI:10.3109/10253890.2011.604751 · 3.46 Impact Factor
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ABSTRACT: Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients' quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo-pituitary-adrenocortical (HPA) axis and/or diminished raphe-hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin 1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naive subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naive and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naive and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under the conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2011; 36(6):1305-16. DOI:10.1038/npp.2011.18 · 7.83 Impact Factor