Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We assessed whether daily separation of Mongolian gerbils (Meriones unguiculatus) from mothers and siblings during postnatal days 4-20 would produce behavioral and neurochemical changes in adulthood that parallel some features of depression in humans. Neonatal separation altered the behavior of adult females in the open field test but not in the tail suspension test, and did not affect behavior of males. Separated males, but not females, showed a significant decrease in hippocampal brain derived neurotrophic factor (BDNF) relative to controls. Western blot and optical densitometry measurements in the hippocampus did not reveal significant group differences in synaptophysin levels in either sex, but there was a tendency toward decreased levels of synaptophysin in the entire hippocampus as well as the CA1 hippocampal subregion of separated males. Repeated separation of neonates from mothers and siblings led to subtle behavioral and neurochemical changes during adulthood that were expressed differently in male and female gerbils.
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PMID:Repeated neonatal separation results in different neurochemical and behavioral changes in adult male and female Mongolian gerbils. 1804 94

The sigma1 receptor is an intracellular molecule that shares no homology with any mammalian proteins. sigma1 receptors normally localize at the endoplasmic reticulum and regulate a variety of signal transductions including intracellular Ca2+ dynamics and neurotrophic factor signaling. In the brain, sigma1 receptors are known to regulate the activity of diverse ion channels via protein-protein interactions. Accumulated evidences strongly indicate that the activation/upregulation of sigma1 receptors promotes the neuronal differentiation as well as a robust antiapoptotic action. In animals, sigma1 receptor agonists exhibit an antidepressant-like action. Furthermore, the agonists enhanced neuronal survival eventhough they were administered several hours after a brain ischemia. Thus, primary clinical targets of sigma1 receptor ligands are proposed to include stroke, neurodegenerative disorders and depression. Ligands for the sigma1 receptor may constitute a new class of therapeutic drugs targeting an endoplasmic reticular protein.
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PMID:An update on the development of drugs for neuropsychiatric disorders: focusing on the sigma 1 receptor ligand. 1807 69

Depressive disorders have a worldwide high prevalence. Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) antidepressant, has been widely prescribed for depression during pregnancy and/or lactation. Since serotonin is a neurotrophic factor, the use of FLX by mothers could disrupt brain development resulting in behavioral alterations in their progeny. The aim of the present study was to evaluate the effects of developmental FLX exposure on sexual behavior, as well as on endocrine parameters, of male mice. Swiss dams were treated daily, by gavage, with 7.5 mg/kg of FLX during pregnancy and lactation. Male pups were tested for copulatory behavior and sexual incentive motivation. Male pups also had their anogenital distance, plasmatic testosterone concentration and testis, epididymis, seminal vesicle and pituitary wet weights assessed. Copulatory behavior, anogenital distance, plasmatic testosterone concentration and organs wet weights were not affected by FLX exposure. However, this exposure eliminated preference for a sexual incentive on the sexual incentive motivation test, which indicates reduced sexual motivation, a classic side effect of SSRIs in humans who take these antidepressants.
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PMID:Maternal exposure to the antidepressant fluoxetine impairs sexual motivation in adult male mice. 1845 68

Although the brain derived neurotrophic factor (BDNF) has been mainly investigated in the context of depression and anxiety disorders, several studies also suggest an association between BDNF and smoking. BDNF represents a protein which crucially influences several processes in the cell ranging from growth to apoptosis. A functional variant of the BDNF gene - the BDNF Val66Met polymorphism - is one of the main targets in BDNF research because of its influence on BDNF secretion. Recently an association between the 66Met allele and smoking has been reported in a sample of 320 Caucasians. The aim of the present study was to replicate this association in a sample nearly twice as large consisting of N=614 German Caucasian participants. A link between smoking and the BDNF Val66Met polymorphism could not be found in our data.
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PMID:The BDNF Val66Met polymorphism and smoking. 1860 52

Mounting evidence shows that the brain derived neurotrophic factor (BDNF) plays a crucial role in synaptic plasticity. Due to its potential involvement in psychiatric diseases like depression and anxiety disorders BDNF lately became a major target in research. A functional variant of the BDNF gene--the BDNF Val66Met polymorphism--is of particular interest, because it influences the BDNF secretion which is followed by signaling at the TrkB receptor leading to dendritic growth of neurons. Findings from genetic association studies in humans yield heterogenous results with respect to the question of which allele represents a potential risk factor for an affective disorder. Although structural MRT studies revealed that the 66Met variant is associated with smaller hippocampi and could therefore present the risk allele, fMRI studies investigating the processing of emotion with respect to the BDNF Val66Met polymorphism are lacking. N=37 healthy female subjects participated in an fMRI experiment with an affective startle reflex paradigm. Carriers of the 66Met variant showed stronger amygdala activation in the right hemisphere in response to emotional stimuli compared to neutral stimuli. The results of this study add to growing literature, showing that it is the 66Met, which is associated with higher trait anxiety.
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PMID:The BDNF Val66Met polymorphism affects amygdala activity in response to emotional stimuli: evidence from a genetic imaging study. 1860 5

Several lines of knockout (KO) mice have been evaluated as models of depression-related behavioral and neurobiological changes, and used to investigate molecular and cellular mechanisms underlying the activity of antidepressant drugs. Adult neurogenesis and brain 5-hydroxytryptamine (5-HT)/neurotrophic factor interactions have recently attracted great interest in relation to the mechanism of action of antidepressant drugs. The present review focuses primarily on genetic manipulation of the serotoninergic (5-HT) system. Basal neurochemical and behavioral changes occurring in mice lacking the 5-HT transporter (SERT), which is the main target of antidepressant drugs, as well as in those lacking G protein-coupled serotonin receptors (e.g. 5-HT1B, 5-HT1A, and 5-HT4 receptors) are described and evaluated. The importance of KO mice for neurotrophic factors, particularly for brain-derived neurotrophic factor and its high-affinity receptor (R-TrkB), is also addressed. Constitutive KO, tissue specific, or inducible KO mice targeting both 5-HT and brain-derived neurotrophic factor systems may potentially make an important contribution to knowledge of the pathophysiology and treatment of depression.
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PMID:Mutant mouse models and antidepressant drug research: focus on serotonin and brain-derived neurotrophic factor. 1917 48

Previous reports have shown that antidepressants increase neuronal cell proliferation and enhance neuroplasticity both in vivo and in vitro. This study investigated the direct effects of one such antidepressant, fluoxetine , on cell proliferation and on the production of neurotrophic factors in neuronal precursors derived from human embryonic stem cells (hESCs; H9). Fluoxetine induced the differentiation of neuronal precursors, strongly enhancing neuronal characteristics. The rate of proliferation was higher in fluoxetine -treated cells than in control cells, as determined by MTT [3(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide] assay. The CPDL (cumulative population doubling level) of the fluoxetine-treated cells was significantly increased in comparison to that of control cells (p<.001). Bromodeoxyuridine incorporation and staurosporine-induced apoptosis assays were elevated in fluoxetine-treated cells. Quantitative RT-PCR analysis revealed no significant differences in the expression of neurotrophic factors, brain-derived neurotrophic factor (BDNF);glial-derived neurotrophic factor (GDNF) and cAMP-responsive element-binding protein (CREB) between cells treated with fluoxetine for two weeks and their untreated counterparts. These results may help elucidate the mechanism of action of fluoxetine as a therapeutic drug for the treatment of depression. Data presented herein provide more evidence that, in addition to having a direct chemical effect on serotonin levels, fluoxetine can influence hESC-derived neuronal cells by increasing cell proliferation, while allowing them to maintain their neuronal characteristics.
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PMID:Increased cellular turnover in response to fluoxetine in neuronal precursors derived from human embryonic stem cells. 1959 7

The chronic mild stress (CMS) model has been used as an animal model of depression which induces anhedonic behavior in rodents. The present study was aimed to evaluate the behavioral and physiological effects of administration of beta-carboline harmine in rats exposed to CMS procedure. To this aim, after 40 days of exposure to CMS procedure, rats were treated with harmine (15 mg/kg/day) for 7 days. In this study, sweet food consumption, adrenal gland weight, adrenocorticotrophin hormone (ACTH) levels, and hippocampal brain-derived-neurotrophic factor (BDNF) protein levels were assessed. Our findings demonstrated that chronic stressful situations induced anhedonia, hypertrophy of adrenal gland weight, increase ACTH circulating levels in rats and increase BDNF protein levels. Interestingly, treatment with harmine reversed anhedonia, the increase of adrenal gland weight, normalized ACTH circulating levels and BDNF protein levels. Finally, these findings further support the hypothesis that harmine could be a new pharmacological tool for the treatment of depression.
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PMID:Effects of beta-carboline harmine on behavioral and physiological parameters observed in the chronic mild stress model: further evidence of antidepressant properties. 1977

Preclinical and clinical studies demonstrate that neurotrophic factors play critical roles in the etiology and treatment of depression. While the mechanisms underlying the therapeutic efficacy of antidepressants remain unknown, increasing evidence supports a role for increased trophic support in the treatment of depression. Furthermore, antidepressants block or reverse stress-induced down regulation of neurotrophic factor expression in limbic and cortical nuclei involved in the underlying pathophysiology of depression. Thus, components of neurotrophic factor-mediated signaling cascades or the signal transduction pathways that regulate neurotrophic factor expression may provide additional targets for the development of novel, more efficacious antidepressant drugs.
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PMID:Future Antidepressant Targets: Neurotrophic Factors and Related Signaling Cascades. 1980 72

Treatment of depression has been dominated by monoamine hypotheses for nearly half a century. Although the ultimate downstream targets of manipulation of biogenic amine transport and metabolism are signal transduction cascades, neurotrophic factors and ultimately genomic fine-tuning, much of drug development has remained focused on strategies to facilitate a rapid initial augmentation of synaptic neurotransmitter levels. Both monoaminergic agents that are highly specific in their target receptor stimulation and agents that modify multiple monoamine systems will move through the stages of drug development in coming years. Furthermore, recent landmark successes and initial pilot data indicates that small molecule peptide receptor antagonists for substance P, corticotrophin releasing factor and eventually others will be of increasing importance, since they may more subtlety modulate neurotransmission and only act on already deranged neural circuits. Eventually treatment strategies may begin to target intracellular kinase and phosphatase activity and other signal systems responsible for transporter and receptor trafficking patterns, as well as via more direct pathways toward mobilization of neurotrophic factor activity. In the near future however, refinement of monoamine strategies to treat depression will continue to guide thinking and development of novel drugs for depression. This review focuses primarily on developments relevant for the evolution of monaminergic and neuropeptide-based drugs for depression.
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PMID:Monoamine and neuropeptide-related function: prospects for novel therapeutics of depression. 1981 Oct 3


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