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)

Drugs of abuse cause long-lasting changes in the brain that underlie the behavioral abnormalities associated with drug addiction. Similarly, experience can induce memory formation by causing stable changes in the brain. Over the past decade, the molecular and cellular pathways of drug addiction, on the one hand, and of learning and memory, on the other, have converged. Learning and memory and drug addiction are modulated by the same neurotrophic factors, share certain intracellular signaling cascades, and depend on activation of the transcription factor CREB. They are associated with similar adaptations in neuronal morphology, and both are accompanied by alterations in synaptic plasticity (e.g., long-term potentiation, long-term depression) at particular glutamatergic synapses in the brain. There has also been recent convergence in the brain regions now considered important sites for molecular and cellular plasticity underlying addiction and memory. Complex circuits involving the hippocampus, cerebral cortex, ventral and dorsal striatum, and amygdala are implicated both in addiction and in learning and memory. The complexity of the plasticity that occurs in these circuits can be illustrated by CREB, which induces very different behavioral effects in these various brain regions. A better understanding of the molecular and cellular adaptations that occur in these neural circuits may lead to novel interventions to improve memory and combat addiction in humans.
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PMID:Common molecular and cellular substrates of addiction and memory. 1255 41

Depression is a highly prevalent condition in adult population. Research on the mechanism of action of antidepressant drugs is also expected to allow a better comprehension about its etiopathogenesis. First theories about neurobiology of depression pointed out the monoaminergic modifications elicited by antidepressants. However, these changes could not be correlated with the latency of action observed in their clinical use. In 1997, with the formulation of genomic theory of depression, old theories and new knowledge about cellular and molecular effects of antidepressant treatment became congruent. The main goal of this paper is to review this theory and the scientific papers in which it is supported. Scientific evidences against genomic theory of antidepressant action are also mentioned. CREB's participation in antidepressant response, as well as BDNF trophic effect and their intracellular signaling pathways are described, as many of these molecules could become targets for the action of new antidepressants.
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PMID:[New perspectives of the mechanism of action of antidepressants arised from genomic theory of depression]. 1269 Apr 7

We report evidence that mitochondrially produced superoxide (O(2)(-)) is involved in signaling in hippocampal neurons by examining the relationship between strong but physiological increases in cytosolic free Ca(2+), mitochondrial calcium accumulation, O(2)(-) production, and CREB phosphorylation. Strong depolarization-induced Ca(2+) entry through NMDA or L-type Ca(2+) channels evoked large Ca(2+) transients, a sustained increase in O(2)(-), and a large rise in nuclear CaM and pCREB. Under these conditions, inhibition of mitochondrial Ca(2+) uptake and consequent O(2)(-) production suppressed Ca(2+) entry-induced pCREB elevation, indicating that O(2)(-) produced by mitochondria supports CREB phosphorylation. Similarly, inhibiting mitochondrial respiration blocked O(2)(-) production and also depressed the elevation of pCREB. Blocking calcineurin reversed this depression. We conclude that strong Ca(2+) entry promotes mitochondrial calcium accumulation and the subsequent enhancement of mitochondrial O(2)(-) production, which in turn prolongs the lifetime of pCREB by suppressing calcineurin-dependent pCREB dephosphorylation.
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PMID:Calcium-dependent mitochondrial superoxide modulates nuclear CREB phosphorylation in hippocampal neurons. 1469 72

Protein kinases critically regulate synaptic plasticity in the mammalian hippocampus. Cyclic-AMP dependent protein kinase (PKA) is a serine-threonine kinase that has been strongly implicated in the expression of specific forms of long-term potentiation (LTP), long-term depression (LTD), and hippocampal long-term memory. We review the roles of PKA in activity-dependent forms of hippocampal synaptic plasticity by highlighting particular themes that have emerged in ongoing research. These include the participation of distinct isoforms of PKA in specific types of synaptic plasticity, modification of the PKA-dependence of LTP by multiple factors such as distinct patterns of imposed activity, environmental enrichment, and genetic manipulation of signalling molecules, and presynaptic versus postsynaptic mechanisms for PKA-dependent LTP. We also discuss many of the substrates that have been implicated as targets for PKA's actions in hippocampal synaptic plasticity, including CREB, protein phosphatases, and glutamatergic receptors. Future prospects for shedding light on the roles of PKA are also described from the perspective of specific aspects of synaptic physiology and brain function that are ripe for investigation using incisive genetic, cell biological, and electrophysiological approaches.
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PMID:Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein kinases. 1501 27

The mechanism of action of electroconvulsive seizures (ECS), one of the most effective treatments of major depression, may involve the regulation of gene expression. Chromatin remodeling at gene promoter regions is increasingly recognized as a key control point of gene expression and may, therefore, partly mediate acute and chronic effects of ECS on gene activity. Here, we assayed how posttranslational modifications of histones, a major form of chromatin remodeling, are altered at several gene promoters in rat hippocampus at 30 min, 2 hr, and 24 hr after acute or repeated ECS. We performed chromatin immunoprecipitation assays to measure levels of histone H3 and H4 acetylation and phosphoacetylation at the promoters of the c-fos, BDNF, and CREB (cAMP response element-binding protein) genes, the expression of which is altered by ECS. We found that, with few exceptions, levels of H4 acetylation correlated with mRNA levels for c-fos, BDNF, and CREB throughout the acute and chronic time course study, whereas acetylation and phosphoacetylation of H3 were detected more selectively. Our findings suggest that the chronic downregulation of c-fos transcription, observed in this study, may be achieved at the level of H4 acetylation, whereas chronic upregulation of BDNF transcription may be sustained via control of H3 acetylation, selectively at the BDNF P3 and P4 promoters. These data provide the first in vivo demonstration of the involvement of chromatin remodeling in ECS-induced regulation of gene expression in the brain and will help in understanding the mechanisms underlying the efficacy of ECS in the treatment of depression.
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PMID:Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. 1520 33

Previously, we reported an ability of NE to promote processes of plasticity in neuroblastoma cells, as observed by morphological changes such as an elongated granule-rich cell body and neuritegenesis, in addition to a progressive decrease in the pluripotent marker Oct4 and an increase in the growth cone marker GAP-43. This was accompanied by the induction of three plasticity genes forming a functional cluster, the cell adhesion molecule L1 (CAM-L1), laminin, and CREB, all involved in neuronal plasticity and neurite outgrowth. In the present study, we hypothesized that the regulation of CAM-L1, laminin, and CREB/pCREB by NE could mediate processes of plasticity in the mode of action of antidepressants, as well as in the long-term effects of stress, in rats, given the association of both with NE alterations and neuronal plasticity. In the first experiment, rats were chronically administered with antidepressants (21 days). In the second experiment, rats were exposed to chronic stress and examined 4 months later, a model shown to exhibit behavioral indices of stress. We found brain region-specific alterations in mRNA and protein levels of CAM-L1, laminin, and pCREB in rats chronically treated with the noradrenergic antidepressant desipramine and, to a lesser extent, in those treated with fluoxetine. Stressed rats presented a decrease in CAM-L1, laminin, and pCREB, specifically in brain areas implicated in stress. Our findings suggest that noradrenergic-regulated plasticity genes such as CAM-L1, laminin, and CREB play an important role both in stress and in the treatment of depression.
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PMID:Antidepressants and prolonged stress in rats modulate CAM-L1, laminin, and pCREB, implicated in neuronal plasticity. 1590 95

Prostate apoptosis response 4 (Par-4) is a leucine zipper containing protein that plays a role in apoptosis. Although Par-4 is expressed in neurons, its physiological role in the nervous system is unknown. Here we identify Par-4 as a regulatory component in dopamine signaling. Par-4 directly interacts with the dopamine D2 receptor (D2DR) via the calmodulin binding motif in the third cytoplasmic loop. Calmodulin can effectively compete with Par-4 binding in a Ca2+-dependent manner, providing a route for Ca2+-mediated downregulation of D2DR efficacy. To examine the importance of the Par-4/D2DR interaction in dopamine signaling in vivo, we used a mutant mouse lacking the D2DR interaction domain of Par-4, Par-4DeltaLZ. Primary neurons from Par-4DeltaLZ embryos exhibit an enhanced dopamine-cAMP-CREB signaling pathway, indicating an impairment in dopamine signaling in these cells. Remarkably, Par-4DeltaLZ mice display significantly increased depression-like behaviors. Collectively, these results provide evidence that Par-4 constitutes a molecular link between impaired dopamine signaling and depression.
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PMID:Par-4 links dopamine signaling and depression. 1605 Nov 41

Affective disorders are common psychiatric illnesses characterized by marked gender-related prevalence. Recent evidence links chronic stress and dysregulation of neurotrophin signaling with the development of depression, while novel theories suggest that antidepressants may act by promoting intracellular adaptations linked to neuroplasticity. Although selective serotonin reuptake inhibitors (SSRIs) efficaciously improve a variety of dysfunctions in males, their neuroendocrine effects and intracellular signaling patterns in females are not well determined. Here we show that chronic footshock stress (21 days) promotes HPA axis hyperactivity (as seen by the increased FOS-ir in the paraventricular hypothalamic nucleus (PVN), plasma corticosterone and adrenal hypertrophy), reduces hippocampal BrdU immunoreactivity and suppresses cortical-limbic CREB phosphorylation in female rats. Long-term citalopram treatment, in contrast, attenuates stress-induced elevation of corticosterone levels and adrenal hypertrophy, although it does not reverse footshock-mediated induction of FOS-ir in the PVN, inhibition of CREB phosphorylation and reduction of hippocampal BrdU-labeling. Moreover, citalopram administration was also associated with significant hypophagic effects and inhibition of CREB phosphorylation. These data suggest that, in female rats, normalization of chronic stress-induced HPA axis abnormalities may represent an initial phase of citalopram-mediated therapeutic actions and despite this SSRI's apparent lack of effects on neuroplasticity, we cannot exclude the possibility that some neurochemical adaptations occur in a later stage which may require more than 3 weeks of treatment to manifest.
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PMID:Unique patterns of FOS, phospho-CREB and BrdU immunoreactivity in the female rat brain following chronic stress and citalopram treatment. 1630 18

Early hypotheses on the pathophysiology of mood disorders were based on aberrant intrasynaptic concentrations of the neurotransmitters serotonin and norepinephrine. However, recent neuroimaging and post mortem morphometric studies demonstrated selective structural and morphological (macroscopic and microscopic) changes across various limbic and non-limbic circuits in the brains of depressed patients. Recently, these two types of observations seem to converge at the cellular and molecular level. It has been revealed, that stress and antidepressant treatment have an opposite effect on the intracellular signaling, transcription factors and target genes. In some cases, the factors that are influenced by antidepressants (e.g. cAMP-CREB cascade, BDNF) have also been identified as important mediators of learning and memory. An evolving new hypothesis in the pathophysiology and treatment of depression involves adaptation or plasticity of neural systems. Depression could result from an inability to make the appropriate adaptive responses to stress or aversive stimuli. It is possible that antidepressant treatment could oppose these adverse cellular effects, which may be regarded as a loss of neural plasticity, by blocking or reversing the atrophy of neurons and by increasing cell survival and function.
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PMID:[Neuroplasticity and depression]. 1638 29

Major depressive disorder is a severe clinical problem across the globe, with a lifetime risk of 10%-30% for women and 7%-15% for men. The World Health Organization ranks major depression at the top of the list in terms of disease burden, and this burden is expected to rise in the next decade as the prevalence of the disorder grows. Since the late 1950s, a wide range of antidepressant medications targeting the monoamine systems has been available to alleviate the symptoms of major depressive disorder. Although widely prescribed, such antidepressant medications are accompanied by a delay in effectiveness, as well as varied side effects. Therefore, further characterization of the biological mechanisms behind their function is crucial for the development of new and more effective treatments. One protein that could serve as a convergence point for multiple classes of antidepressant drugs is the transcription factor CREB (cyclic adenosine monophosphate response element binding protein). CREB is upregulated by chronic antidepressant treatment, and increasing CREB levels in rodent models results in antidepressant-like behaviors. Furthermore, postmortem studies indicate that CREB levels are increased in subjects taking antidepressants at the time of death. However, not all antidepressants increase CREB levels and/or activity, and reducing CREB levels in some brain regions also results in antidepressant-like behaviors. This review attempts to consolidate the information relevant to the structure and function of the CREB protein and describe how this relates to the mechanism of antidepressant drugs. Animal models in which CREB function is enhanced, by overexpression of the protein, or reduced, by expression of mutant forms of the protein or through gene deletion experiments, are summarized in terms of identifying a role for CREB in behavioral responses in depression tests that were originally designed to evaluate antidepressant efficacy. Human postmortem and genetic studies that implicate CREB in depression and antidepressant efficacy are also discussed.
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PMID:The role of CREB in depression and antidepressant treatment. 1645 82


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