R S Duman

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..These findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response...

..Characterization of a novel signalling pathway also identifies new cellular targets that could result in rapid and efficacious antidepressant actions without the side effects of ketamine...

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..A brief overview of this work and the specific neurotrophic factors involved are discussed in this review...

..However, caution is warranted, as results from animal studies are not always predictive of therapeutic actions in humans...

..Below we review the current data supporting the neurotrophic hypothesis of depression, and discuss potential approaches to pharmacologically upregulate neurotrophic/growth factor signaling to elicit antidepressant responses...

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..These findings comprise a novel conceptual framework for future studies of the etiology of mood disorders and for the development of novel therapeutic interventions...

..This article reviews the primary work leading to a neurotrophic hypothesis of depression and antidepressant action and the cellular mechanisms and signal transduction pathways that underlie these effects...

..The possibility that these atypical antipsychotic drugs also influence the molecular determinants of synaptic plasticity that are involved in the response to drugs used for the treatment of mood disorders, is discussed...

..These findings identify new targets for rapid acting antidepressants that are safer than ketamine. This article is part of a Special Issue entitled 'Anxiety and Depression'...

..This exciting area of research holds promise and potential for further elucidating the pathophysiology of psychiatric illness and for development of novel therapeutic interventions...

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..Interpretation of these effects is complicated by the malaise caused by acute injections of pro-inflammatory cytokines, however. Thus, it is unclear whether cytokines are involved in the etiology of depressive symptoms...

..The results suggest that regulation of activin and Smad signaling may contribute to the actions of antidepressant treatment and may represent novel targets for antidepressant drug development...

..Infusions of BDNF and NT-3 did not influence locomotor activity or passive avoidance. The results provide further support for the hypothesis that BDNF contributes to the therapeutic action of antidepressant treatment...

..BDNF-regulated signaling pathways are thus potential targets for investigation of antidepressant mechanisms...

..Moreover, in the basolateral amygdala, the temporal expression of CREB in relation to learned helplessness training, determines the qualitative outcome in this animal model of depression...

..However, the underlying neurobiological mechanisms that contribute to PPD have not been determined...

..This study demonstrates the utility of microarray analysis of microdissected subregions of limbic brain regions and identifies novel ECS-regulated genes...

..However, little is known about the mechanisms that contribute to this decrease in cell number...

..The intracellular factors by which ADTs and glucocorticoids, causal factors in depression, regulate depression-like behavior remain unclear, but extracellular signal-regulated kinase 1/2 (ERK1/2), upstream of CREB, is a likely candidate...

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..The roles of 5-HT2A receptors and of stress on the BDNF mRNA regulation were also explored...

..The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development...

..These findings indicate that the cAMP-CREB cascade plays an important role in the differentiation and maturation of newborn neurons in hippocampus...

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..These findings indicate that the cAMP-CREB pathway regulates the survival, and possibly the differentiation and function, of newborn neurons...

..However, it is unclear whether this glial loss plays a direct role in the expression of depressive symptoms...

..Upregulation of MKP expression could dampen the actions of ECS, indicating that blockade of the MKPs could enhance the actions of antidepressant treatment...

..This double dissociation demonstrates bidirectional competition that constitutes strong evidence for the parallel operation of distinct memory systems...

..These postmortem and preclinical studies identify MKP-1 as a key factor in MDD pathophysiology and as a new target for therapeutic interventions...

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..This perspective reviews the literature in support of the hypothesis that altered birth of new neurons in the adult brain contributes to the etiology and treatment of depression and considers research strategies to test this hypothesis...

..Together, the results demonstrate that nucleus accumbens CREB-dynorphin influence behavior in the learned helplessness model and suggest that this signaling cascade may contribute to symptoms of depression...

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..Together, these data identify NF-kappaB signaling as a critical mediator of the antineurogenic and behavioral actions of stress and suggest previously undescribed therapeutical targets for depression...

..This study demonstrates the applicability of custom-focused microarray technology in addressing hypothesis-driven questions regarding the action of antidepressants...

..These findings demonstrate that IL-1beta is a critical mediator of the antineurogenic and depressive-like behavior caused by acute and chronic stress...

..The results suggest that the cAMP-CREB cascade could contribute to the actions of neurotransmitters and neurotrophic factors on adult neurogenesis...

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..Aside from this function, beta-catenin is a key effector molecule in the Wnt signaling pathway, serving as a downstream transcription factor...

..These findings are of increasing interest, as they relate to the use of ECT in the treatment of depression, and the specific anesthetic agents that are used...

..This review focuses on intracellular signaling cascades that underlie depression and treatment response...

..CONCLUSIONS: These results demonstrate that over-expression of CREB in hippocampus results in an antidepressant effect and suggest that CREB may serve as a potential molecular target for novel therapeutic agents...

..This information has contributed to novel antidepressant medication development that utilizes adult neurogenesis and gliogenesis as preclinical cellular markers for predicting antidepressant properties of novel compounds...

..Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine...

..These data demonstrate that in cortical neurons, a short PDE4B2 intronic promoter is regulated by CREB, confers cAMP responsitivity and directs PDE4B2 mRNA and protein expression...

..In summary, chronic wheel-running exercise in mice results in antidepressant-like behavioral changes that may involve a BDNF related mechanism similar to that hypothesized for antidepressant drug treatment...

..These results support the functional relevance of neurotrophic mechanisms to depression and extend this idea to include neurotrophic factors in the periphery...

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..Greater appreciation of the convergence of mechanisms between stress, depression, and neuroplasticity is likely to lead to the identification of novel targets for more efficacious treatments...

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..The ability to express different transgenes within this subpopulation of neuronal precursors provides a powerful system to define the signals regulating the differentiation and survival of adult-generated neurons in the olfactory bulb...

..Modulation of cocaine reward is a novel action of the melanocortin-MC4-R system and could be targeted for the development of new medications for cocaine addiction...

..Gene regulation was confirmed via quantitative real time polymerase chain reaction and in situ hybridization...

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..The custom microarray approach is presented with procedural details for design and production in the context of neurobiological investigations...

..These insights should assist in understanding the pathophysiology of severe mood disorders as well as aid in the development of more effective treatments...

..These data further support a role for the melanocortin-MC4-R neuropeptide system in the biochemical and behavioral effects of cocaine...

..Increases in the vascular density of the SLM could be in response to enhanced metabolic activity in this region. This is supported by the induction of glutamine synthetase and the glutamate transporter GLT1...

..Antidepressants could mediate their effects by increasing neurogenesis and modulating the signaling pathways involved in plasticity and survival...

..Aberrant regulation of neuronal plasticity, including neurogenesis, in the hippocampus and other limbic nuclei may result in maladaptive changes in neural networks that underlie the pathophysiology of MDD...

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..These data demonstrate that PKA inhibition, rather than activation, is the appropriate strategy for restoring prefrontal cortical cognitive abilities in the elderly...

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..This review will focus on the research that has led us to this current understanding of antidepressant action in context with the pathophysiology of depression using examples from basic, preclinical and clinical investigations...

..Finally, there was a significant reduction in cocaine-induced locomotor activity in the CREB bitransgenic mice. These results are consistent with a role for CREB in mediating adaptive changes that occur in response to drugs of abuse...

..We found a significant linkage disequilibrium between the -491A/T and ApoE polymorphisms. However, no direct association was observed between the -491A/T or BH-PEN polymorphism and AD...

..These findings identify fosB gene products as transcription factors critical for molecular, electrophysiological, and behavioral adaptations to motor seizures...

..Although the functional consequences remain unclear, sprouting of the mossy fiber pathway would appear to oppose the actions of stress and could thereby contribute to the therapeutic actions of electroconvulsive seizure therapy...

..in this issue of Molecular Pharmacology, address this question and demonstrate that psychotropic drugs modify specific methyl-CpG-binding proteins that control histone acetylation and gene expression...

..These results suggest that alterations in CREB/BDNF may contribute to the generation of individual differences in stress neurocircuitry, providing a substrate for altered vulnerability to depressive disorders...

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..These results indicate that both dynorphin A and dynorphin B contribute to the effects of stress, and suggest that blockade of kappa-opioid receptors may have therapeutic potential for the treatment of depression...

..These findings establish that chronic stress induces DeltaFosB in several discrete regions of the brain. Such induction could contribute to the long-term effects of stress on the brain...

..These findings demonstrate that exposure to IS, which results in a state of behavioral despair, decreases hippocampal cell proliferation and that this effect can be reversed by fluoxetine treatment...

..These findings identify abnormal gene expression in a discrete region of MDD subjects and contribute to further elucidation of the molecular alterations of this complex mood disorder...

..Because VEGF has been implicated in a variety of diseases, understanding the molecular and cellular specificity of antidepressant-induced VEGF will be crucial to determine its potential as a therapeutic target in depression...

..CRE-mediated transcription may itself contribute to re-establishing homeostasis in the organism through target gene regulation in these regions...

..These studies will further characterize the mechanisms underlying the action of ADT and identify novel drug targets for the development of faster acting and more efficacious medications. ..

..Thus, basic and clinical research is carried out in areas related to anxiety (e.g., panic and post-traumatic stress disorder), obsessive compulsive disorder, schizophrenia, and affective illness. ..

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..Finally, studies to identify the isoforms of cAMP phophodiesterase (PDE4) that catalyzes the breakdown of cAMP are proposed, including regulation of PDE4 isoforms by antidepressant treatment and development of PDE4 null mutant mice. ..

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..Activation of the PKA-CREB cascade and induction of BDNF could mediate long-term adaptations of neuronal function in response to antidepressant treatments. ..