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Brain-Derived Neurotrophic Factor Produces Antidepressant Effects in Behavioral Models of Depression.

Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 05/2002; 22(8):3251-61. DOI: 10.3410/f.1005737.68355
Source: PubMed

ABSTRACT Previous studies demonstrated that antidepressant treatment increases the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampus. The present study was conducted to test the hypothesis that BDNF in the hippocampus produces an antidepressant effect in behavioral models of depression, the learned helplessness (LH) and forced swim test (FST) paradigms. A single bilateral infusion of BDNF into the dentate gyrus of hippocampus produced an antidepressant effect in both the LH and FST that was comparable in magnitude with repeated systemic administration of a chemical antidepressant. These effects were observed as early as 3 d after a single infusion of BDNF and lasted for at least 10 d. Similar effects were observed with neurotrophin-3 (NT-3) but not nerve growth factor. 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.

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    • "In rodents a direct injection of BDNF into the hippocampus diminishes depressive symptoms (Shirayama et al., 2002). Patients with MDD have reduced volumes of the hippocampus and frontal lobes (Dwivedi et al., 2003; Knable et al., 2004; Stockmeier et al., 2004), a sign of neuronal atrophy associated with lower levels of BDNF (Martinowich et al., 2007). "
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    ABSTRACT: Rs6265 single nucleotide polymorphism, which influences brain-derived neurotrophic factor (BDNF) levels in the cortical and subcortical brain structures, may result in distinguished patterns of neural activation during a major depressive disorder (MDD) episode. Valine homozygotes with high levels of BDNF and methionine carriers with lower levels of BDNF may present specific neural correlates of MDD. In our study we have tested differences in blood oxygen level dependant (BOLD) signal between individuals with MDD and healthy controls for both allelic variants. Individuals with MDD (N=37) and healthy controls (N=39) were genotyped for rs6265 and compared separately in each allelic variant for BOLD response in a functional magnetic resonance imaging experiment examining appraisal of emotional scenes. The two allelic variants were also compared separately for both individuals with MDD and healthy controls. In the homozygous valine group MDD was associated with decreased neural activation in areas responsible for cognitive appraisal of emotional scenes. In the methionine group MDD was related to increased activation in subcortical regions responsible for visceral reaction to emotional stimuli. During an MDD episode methionine carriers showed more activation in areas associated with cognitive appraisal of emotional information in comparison to valine homozygotes. Small sample size of healthy controls carrying methionine (N=8). Our results suggest that allelic variations in the rs6265 gene lead to specific neural correlates of MDD which may be associated with different mechanisms of MDD in the two allelic groups. This may have potential importance for screening and treatment of patients. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Affective Disorders 06/2015; 184:239-244. DOI:10.1016/j.jad.2015.06.002 · 3.71 Impact Factor
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    • "The neurotrophic hypothesis of depression is based on clinical and preclinical observations that include three lines of evidence: a low concentration of BDNF in the hippocampus of postmortem samples from depressed suicide victims [74] , depression-related behaviors caused by impaired BDNF signaling in rodent hippocampus [75] [76] , and the antidepressant effects of increased hippocampal BDNF [77] [78] . BDNF is critical for stabilizing synaptic plasticity. "
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    ABSTRACT: Depression is a devastating psychiatric disorder widely attributed to deficient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4-8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplification. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant efficacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modified indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.
    Neuroscience Bulletin 02/2015; 31(1):75-86. DOI:10.1007/s12264-014-1484-6 · 1.83 Impact Factor
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    • "In contrast, Nestler's group demonstrated that BDNF in the ventral tegmental area (VTA)-nucleus accumbens (NAc) pathway is required for depression onset (Eisch et al., 2003; Berton et al., 2006; Nestler and Carlezon, 2006; Krishnan et al., 2007). This suggests that BDNF acts within the VTA-NAc pathway, inducing a depression-like phenotype (Eisch et al., 2003; Berton et al., 2006; Nestler and Carlezon, 2006; Krishnan et al., 2007), whereas it produces antidepressant-like effects in the hippocampus and PFC (Nestler et al., 2002; Shirayama et al., 2002; Duman and Monteggia, 2006). Currently, there are no reports on the relationship between BDNF-TrkB signaling and dendritic changes in the hippocampus, PFC, and NAc, and the antidepressant action of TrkB ligands. "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), signaling represent potential therapeutic targets for major depressive disorder. The purpose of this study is to examine whether TrkB ligands show antidepressant effects in an inflammation-induced model of depression. In this study, we examined the effects of TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist ANA-12 on depression-like behavior and morphological changes in mice previously exposed to lipopolysaccharide (LPS). Protein levels of BDNF, phospho-TrkB (p-TrkB), and TrkB in the brain regions were also examined. LPS caused a reduction of BDNF in the CA3 and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), whereas LPS increased BDNF in the nucleus accumbens (NAc). Dexamethason suppression tests showed hyperactivity of the hypothalamic-pituitary-adrenal axis in LPS-treated mice. Intraperitoneal (i.p.) administration of 7,8-DHF showed antidepressant effects on LPS-induced depression-like behavior, and i.p. pretreatment with ANA-12 blocked its antidepressant effects. Surprisingly, ANA-12 alone showed antidepressant-like effects on LPS-induced depression-like behavior. Furthermore, bilateral infusion of ANA-12 into the NAc showed antidepressant effects. Moreover, LPS caused a reduction of spine density in the CA3, DG, and PFC, whereas LPS increased spine density in the NAc. Interestingly, 7,8-DHF significantly attenuated LPS-induced reduction of p-TrkB and spine densities in the CA3, DG, and PFC, whereas ANA-12 significantly attenuated LPS-induced increases of p-TrkB and spine density in the NAc. The results suggest that LPS-induced inflammation may cause depression-like behavior by altering BDNF and spine density in the CA3, DG, PFC, and NAc, which may be involved in the antidepressant effects of 7,8-DHF and ANA-12, respectively. © 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/pyu077 · 5.26 Impact Factor
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