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: 6.34). 05/2002; 22(8):3251-61. DOI: 10.3410/f.1005737.68355
Source: PubMed


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.

20 Reads
  • Source
    • "Conversely, antidepressants, including the atypical antidepressant ketamine , have been shown to enhance BDNF production, or even transactivate the BDNF-TrkB (tropomyosin receptor kinase B) receptor, thereby counteracting depressionassociated BDNF-TrkB downregulation (Lindholm and Castrén, 2014). That antidepressants could act through supraspinal BDNF-TrkB activation is supported by data showing that direct intracerebral administration of BDNF itself exerts antidepressant-like effects in validated rodent models of depression (Shirayama et al., 2002). However, it would be irrelevant to infer that an upregulation of BDNF always contributes to an antidepressant action because direct injection of BDNF into the ventral tegmental area was found to cause depression-like behavior, whereas BDNF signaling blockade in the nucleus accumbens produced antidepressant-like effects (Berton et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Numerous reported data support the idea that Brain Derived Neurotrophic Factor (BDNF) is critically involved in both depression and comorbid pain. The possible direct effect of BDNF on pain mechanisms was assessed here and compared with behavioral/neurobiological features of neuropathic pain caused by chronic constriction injury to the sciatic nerve (CCI-SN). Sprague-Dawley male rats were either injected intrathecally with BDNF (3.0ng i.t.) or subjected to unilateral CCI-SN. Their respective responses to anti-hyperalgesic drugs were assessed using the Randall-Selitto test and both immunohistochemical and RT-qPCR approaches were used to investigate molecular/cellular mechanisms underlying hyperalgesia in both models. Long lasting hyperalgesia and allodynia were induced by i.t. BDNF in intact healthy rats like those found after CCI-SN. Acute treatment with the BDNF-TrkB receptor antagonist cyclotraxin B completely prevented i.t. BDNF-induced hyperalgesia and partially reversed this symptom in both BDNF-pretreated and CCI-SN lesioned rats. Acute administration of the anticonvulsant pregabalin, the NMDA receptor antagonist ketamine, the opioid analgesics morphine and tapentadol or the antidepressant agomelatine also transiently reversed hyperalgesia in both i.t. BDNF injected- and CCI-SN lesioned-rats. Marked induction of microglia activation markers (OX42, Iba1, P-p38), proinflammatory cytokine IL-6, NMDA receptor subunit NR2B and BDNF was found in spinal cord and/or dorsal root ganglia of CCI-SN rats. A long lasting spinal BDNF overexpression was also observed in BDNF i.t. rats, indicating an autocrine self-induction, with downstream long lasting TrkB-mediated neuropathic-like pain. Accordingly, TrkB blockade appeared as a relevant approach to alleviate not only i.t. BDNF- but also nerve lesion-evoked neuropathic pain.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 09/2015; DOI:10.1016/j.euroneuro.2015.07.026 · 4.37 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 3.38 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 2.51 Impact Factor
Show more


20 Reads
Available from