The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine

Department of Cell Biology, Duke University, Durham, NC, USA.
Translational Psychiatry (Impact Factor: 5.62). 08/2013; 3(8):e291. DOI: 10.1038/tp.2013.65
Source: PubMed


The importance of reversing brain serotonin (5-HT) deficiency and promoting hippocampal neurogenesis in the mechanisms of action for antidepressants remain highly controversial. Here we examined the behavioral, neurochemical and neurogenic effects of chronic fluoxetine (FLX) in a mouse model of congenital 5-HT deficiency, the tryptophan hydroxylase 2 (R439H) knock-in (Tph2KI) mouse. Our results demonstrate that congenital 5-HT deficiency prevents a subset of the signature molecular, cellular and behavioral effects of FLX, despite the fact that FLX restores the 5-HT levels of Tph2KI mice to essentially the levels observed in wild-type mice at baseline. These results suggest that inducing supra-physiological levels of 5-HT, not merely reversing 5-HT deficiency, is required for many of the antidepressant-like effects of FLX. We also demonstrate that co-administration of the 5-HT precursor, 5-hydroxytryptophan (5-HTP), along with FLX rescues the novelty suppressed feeding (NSF) anxiolytic-like effect of FLX in Tph2KI mice, despite still failing to induce neurogenesis. Thus, our results indicate that brain 5-HT deficiency reduces the efficacy of FLX and that supplementation with 5-HTP can restore some antidepressant-like responses in the context of 5-HT deficiency. Our findings also suggest that feeding latency reductions in the NSF induced by chronic 5-HT elevation are not mediated by drug-induced increments in neurogenesis in 5-HT-deficient animals. Overall, these findings shed new light on the impact of 5-HT deficiency on responses to FLX and may have important implications for treatment selection in depression and anxiety disorders.

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Available from: Benjamin D Sachs, Jul 10, 2014
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    • "The current study did not directly explore the mechanisms through which FLX administration leads to increased proliferation in the habenula and hypothalamus. However, our current results indicate that chronic FLX can increase BDNF mRNA expression in the habenula and hypothalamus, similar to what has been reported previously in the hippocampus (Nibuya et al., 1995; Sachs, Jacobsen, et al., 2013). Prior research has shown that infusions of BDNF can promote cell proliferation and neurogenesis in the hypothalamus and the habenula (Pencea et al., 2001). "
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    ABSTRACT: Chronic treatment with antidepressants has been shown to enhance neurogenesis in the adult mammalian brain. Although this effect was initially reported to be restricted to the hippocampus, recent work has suggested that fluoxetine, a selective serotonin reuptake inhibitor, also promotes neurogenesis in the cortex. However, whether antidepressants target neural progenitor cells in other brain regions has not been examined. Here, we used BrdU labeling and immunohistochemistry with a transgenic mouse line in which nestin+ neural progenitor cells can be inducibly labeled with the fluorescent protein, Tomato, following tamoxifen administration. We investigated the effects of chronic fluoxetine on cell proliferation and nestin+ progenitor cells in periventricular areas in the medial hypothalamus and medial habenula, two brain areas involved in stress and anxiety responses. Our data provide the first in vivo evidence that fluoxetine promotes cell proliferation and neurogenesis and increases the mRNA levels of BDNF in the hypothalamus and habenula. By identifying novel cellular targets of fluoxetine, our results may provide new insight into the mechanisms underlying antidepressant responses. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 10/2014; 18(4). DOI:10.1093/ijnp/pyu029 · 4.01 Impact Factor
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    • "Increased survival or newly generated neurons at baseline [45] Tph2 −/− mouse Normal baseline proliferation in serotonin deficient mice [75] Tph2KI mouse Increased survival or newly generated neurons at baseline with increased numbers of DCX-positive cells Antidepressant action and neurogenesis [57] Flx First shown increase in neurogenesis after prolonged treatment with Flx [14] cAMP cAMP signal transduction cascade contributes to increased neurogenesis as antidepressant response [16] Tianeptine Treatment reduces proliferation of precursor cells in the DG [79] 5-HT1A KO Flx 5-HT1A receptors are required for Flx-induced hippocampal neurogenesis [25] Flx Flx acts solely on type-2a progenitors by increasing the rate of symmetric cell divisions [88] Flx Chronic treatment accelerates maturation and synaptogenesis of immature granule cells [6] SSRI Acute BDNF injection into the hippocampus increases SERT function [83] 5-HT2C Increases proliferation and mediates the antidepressant effect of agomelatine [44] 5-HT1A, 5-HT2C Latency of Flx action due to additive effects of 5HT1A, 2C receptors [47] 5-HT4 KO Flx Flx treatment reverses neuronal maturation (Calbindin expression) with up-regulated 5-HT4 signaling [20] 5-HT2B Pharmacological receptor stimulation mimics SSRI-like response [11] SSRI, TCA Stimulation of angiogenesis and neurogenesis [27] RNAi – SERT Acute SERT silencing increases 5-HT release and neurogenesis and decreases latency in antidepressant action [85] BDNF Decreased BDNF mRNA levels in the DG after 5-HT2A and 2C chronic agonist treatment [18] BDNF BDNF potentiates the effect of SSRI treatment (in vivo intracerebral microdialysis) [71] BDNF SSRI treatment increases BDNF levels released from astrocytes that promote neurogenesis Functional role of serotonin in adult neurogenesis [74] SSRI, BDNF, exercise Exercise-plus-antidepressant challenge lead to increased BDNF levels in the hippocampus [45] Tph2 −/− mouse No running-induced effect on proliferation when serotonin is absent serotonin deficiency has no effect on baseline neurogenesis that may be compensated by altered neurotrophic/BDNF signaling. We have proposed BDNF as candidate for permanent compensation in serotonin deficient mice and recent data already reveal enhanced BDNF mRNA levels in Tph2 −/− and Tph2KI mice [61] [75], although accompanied by increased serotonin fiber density in the hilus. Nevertheless , whether BDNF signaling is related to the clinical features of depression and whether distinct antidepressants directly affect BDNF equally to serotonin remains unknown. "
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    ABSTRACT: Serotonin is probably best known for its role in conveying a sense of contentedness and happiness. It is one of the most unique and pharmacologically complex monoamines in both the peripheral and central nervous system (CNS). Serotonin has become in focus of interest for the treatment of depression with multiple serotonin-mimetic and modulators of adult neurogenesis used clinically. Here we will take a broad view of serotonin from development to its physiological role as a neurotransmitter and its contribution to homeostasis of the adult rodent hippocampus. This chapter reflects the most significant findings on cellular and molecular mechanisms from neuroscientists in the field over the last two decades. We illustrate the action of serotonin by highlighting basic receptor targeting studies, and how receptors impact brain function. We give an overview of recent genetically modified mouse models that differ in serotonin availability and focus on the role of the monoamine in antidepressant response. We conclude with a synthesis of the most recent data surrounding the role of serotonin in activity and hippocampal neurogenesis. This synopsis sheds light on the mechanisms and potential therapeutic model by which serotonin plays a critical role in the maintenance of mood.
    Behavioural Brain Research 08/2014; DOI:10.1016/j.bbr.2014.07.038 · 3.03 Impact Factor
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    • "In addition, 5-HT is an initial signal in the differentiation of neuronal precursor cells into neurons. In vivo studies have revealed that 5-HT plays a crucial role in the neurogenesis of the hippocampus [17]. "
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    ABSTRACT: microRNAs (miRNA), a sort of noncoding RNAs widely distributed in eukaryotic cells, could regulate gene expression by inhibiting transcription or translation. They were involved in important physiological and pathological processes including growth, development, and occurrence and progression of diseases. miRNAs are crucial for the development of the nervous system. Recent studies have demonstrated that some miRNAs play important roles in the occurrence and development of ischemic cerebrovascular diseases such as stroke and were also involved in the occurrence and development of poststroke depression (PSD). Herein, studies on the role of miRNAs in the cerebral ischemia and PSD were reviewed, and results may be helpful for the diagnosis and prognosis of cerebral ischemia and PSD with miRNAs in clinical practice.
    The Scientific World Journal 12/2013; 2013(4):459692. DOI:10.1155/2013/459692 · 1.73 Impact Factor
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