Article

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

Yale University, New Haven, Connecticut, United States
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

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 animal studies with a chronic unpredictable stress model of depression, BDNF levels were decreased in different hippocampal regions[74]. BDNF administered directly into the hippocampus showed antidepressant effects in behavioral models of depression in rats[75], and antidepressant agents increased BDNF levels in the hippocampus and frontal cortex[74,76]. In humans, meta-analyses consistently found reduced serum BDNF concentrations in patients with MDD compared to healthy controls and an increase in BDNF levels with successful antidepressant treatment[77]. "
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    ABSTRACT: Therapeutic sleep deprivation (SD) is a rapid acting treatment for major depressive disorder (MDD). Within hours, SD leads to a dramatic decrease in depressive symptoms in 50–60% of patients with MDD. Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD. Yet, up to now, the neurobiological basis of the antidepressant effect, which is most likely different from today’s first-line treatments, is not sufficiently understood. This article puts the idea forward that sleep/wake-dependent shifts in synaptic plasticity, i.e. the neural basis of adaptive network function and behavior, represent a critical mechanism of therapeutic SD in MDD. Particularly, this article centers on two major hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, and on how they can be integrated into a novel synaptic plasticity model of therapeutic SD in MDD. As a major component, the model proposes that therapeutic SD, by homeostatically enhancing cortical synaptic strength, shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP) in patients with MDD in a more favorable window of associative plasticity. Research on the molecular effects of SD in animals and humans, including observations in the neurotrophic, adenosinergic, monoaminergic, and glutamatergic system, provides some support for the hypothesis of associative synaptic plasticity facilitation after therapeutic SD in MDD. The model proposes a novel framework for a mechanism of action of therapeutic SD that can be further tested in humans based on non-invasive indices and in animals based on direct studies of synaptic plasticity. Further determining the mechanisms of action of SD might contribute to the development of novel fast acting treatments for MDD, one of the major health problems worldwide.
    Full-text · Article · Nov 2015 · Sleep Medicine Reviews
    • "To more directly examine the causal involvement of BDNF in antidepressant responses, Siuciak and colleagues infused BDNF protein directly into the midbrain and observed an antidepressant-like effect in rodents (Siuciak et al., 1997). Subsequent work showed that a single bilateral infusion of a low dose of BDNF directly into the DG or CA3, but not CA1, region of the hippocampus was sufficient to induce an antidepressant-like effect within three days (Shirayama et al., 2002), suggesting that these regions may be key regions for antidepressant effects acting through BDNF. In this latter study, the antidepressant effects of BDNF were suggested to be mediated by TrkB activation of mitogen-activated protein kinase kinase (MEK), acting through the extracellular signal-regulated protein kinase (ERK) pathway. "
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    ABSTRACT: How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knock out mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an essential determinant of antidepressant efficacy.
    No preview · Article · Oct 2015 · Neuropharmacology
    • "BDNF regulates synaptic neuronal survival and peripheral and central neuroplasticity (Binder and Scharfman 2004). It has been studied in pathological conditions such as depression and chronic pain (Hu and Russek 2008; Shirayama et al. 2002). In healthy subjects, the modulating effect of BDNF on the nervous system is gender dependent (Stefani et al. 2012). "
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    ABSTRACT: Aims: Epidemiological studies show that painful disorders are more prevalent in women than in men, and the transcranial direct current stimulation (tDCS) technique has been tested in chronic pain states. We explored the effect of tDCS on pain behavior and brain-derived neurotrophic factor (BDNF) levels in ovariectomized rats. Main methods: Forty-five female Wistar adult rats were distributed into five groups: control (CT), ovariectomy + tDCS (OT), ovariectomy + sham tDCS (OS), sham ovariectomy + tDCS (ST), and sham ovariectomy+shamtDCS (SS). The rats were subjected to cathodal tDCS. The vaginal cytology and the estradiol levels confirmed the hormonal status. In addition, nociceptive behavior was evaluated using the tail-flick, von Frey, and hot-plate tests, as well as the BDNF levels in the serum, hypothalamus, hippocampus, spinal cord, and cerebral cortex. One-way analysis of variance (ANOVA) or two-way ANOVA was used for statistical analysis, followed by the Bonferroni, and P-value b 0.05 was considered significant. Key findings: The ovariectomized animals presented a hypersensitivity response in the hot-plate (P b 0.01) and von Frey (P b 0.05) tests, as well as increased serum BDNF (P b 0.05) and decreased hypothalamic BDNF (P b 0.01) levels. The OT, OS, ST, and SS groups showed decreased hippocampal BDNF levels as compared with the control group (P b 0.001). The interaction between tDCS and ovariectomy on the cortical BDNF levels (P b 0.01) was observed. Significance: The ovariectomy induced nociceptive hypersensitivity and altered serum and hypothalamic BDNF levels. The cathodal tDCS partially reversed nociceptive hypersensitivity.
    No preview · Article · Oct 2015 · Life sciences
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