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      The Role of BDNF, Leptin, and Catecholamines in Reward Learning in Bulimia Nervosa

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          Abstract

          Background:

          A relationship between bulimia nervosa and reward-related behavior is supported by several lines of evidence. The dopaminergic dysfunctions in the processing of reward-related stimuli have been shown to be modulated by the neurotrophin brain derived neurotrophic factor (BDNF) and the hormone leptin.

          Methods:

          Using a randomized, double-blind, placebo-controlled, crossover design, a reward learning task was applied to study the behavior of 20 female subjects with remitted bulimia nervosa and 27 female healthy controls under placebo and catecholamine depletion with alpha-methyl-para-tyrosine (AMPT). The plasma levels of BDNF and leptin were measured twice during the placebo and the AMPT condition, immediately before and 1 hour after a standardized breakfast.

          Results:

          AMPT–induced differences in plasma BDNF levels were positively correlated with the AMPT–induced differences in reward learning in the whole sample ( P=.05). Across conditions, plasma brain derived neurotrophic factor levels were higher in remitted bulimia nervosa subjects compared with controls (diagnosis effect; P=.001). Plasma BDNF and leptin levels were higher in the morning before compared with after a standardized breakfast across groups and conditions (time effect; P<.0001). The plasma leptin levels were higher under catecholamine depletion compared with placebo in the whole sample (treatment effect; P=.0004).

          Conclusions:

          This study reports on preliminary findings that suggest a catecholamine-dependent association of plasma BDNF and reward learning in subjects with remitted bulimia nervosa and controls. A role of leptin in reward learning is not supported by this study. However, leptin levels were sensitive to a depletion of catecholamine stores in both remitted bulimia nervosa and controls.

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          Most cited references44

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          BDNF regulates eating behavior and locomotor activity in mice.

          Brain-derived neurotrophic factor (BDNF) was studied initially for its role in sensory neuron development. Ablation of this gene in mice leads to death shortly after birth, and abnormalities have been found in both the peripheral and central nervous systems. BDNF and its tyrosine kinase receptor, TrkB, are expressed in hypothalamic nuclei associated with satiety and locomotor activity. In heterozygous mice, BDNF gene expression is reduced and we find that all heterozygous mice exhibit abnormalities in eating behavior or locomotor activity. We also observe this phenotype in independently derived inbred and hybrid BDNF mutant strains. Infusion with BDNF or NT4/5 can transiently reverse the eating behavior and obesity. Thus, we identify a novel non-neurotrophic function for neurotrophins and indicate a role in behavior that is remarkably sensitive to alterations in BDNF activity.
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            Toward an objective characterization of an anhedonic phenotype: a signal-detection approach.

            Difficulties in defining and characterizing phenotypes has hindered progress in psychiatric genetics and clinical neuroscience. Decreased approach-related behavior and anhedonia (lack of responsiveness to pleasure) are considered cardinal features of depression, but few studies have used laboratory-based measures to objectively characterize these constructs. To assess hedonic capacity in relation to depressive, particularly anhedonic, symptoms, 62 participants completed a signal-detection task based on a differential reinforcement schedule. Anhedonia was operationalized as decreased reward responsiveness. Unequal frequency of reward between two correct responses produced a response bias (i.e., a systematic preference to identify the stimulus paired with the more frequent reward). Subjects with elevated depressive symptoms (Beck Depression Inventory scores >/= 16) failed to show a response bias. Impaired reward responsiveness predicted higher anhedonic symptoms 1 month later, after controlling for general negative affectivity. Impaired tendency to modulate behavior as a function of prior reinforcement might underline diminished hedonic capacity in depression. When applied to a clinical population, objective assessments of participants' propensity to modulate behavior as a function of reward might provide a powerful tool for improving the phenotypic definition of depression and thus offer a reliable behavioral screening approach for neuroscience studies of depression.
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              A de novo mutation affecting human TrkB associated with severe obesity and developmental delay.

              An 8-year-old male with a complex developmental syndrome and severe obesity was heterozygous for a de novo missense mutation resulting in a Y722C substitution in the neurotrophin receptor TrkB. This mutation markedly impaired receptor autophosphorylation and signaling to MAP kinase. Mutation of NTRK2, which encodes TrkB, seems to result in a unique human syndrome of hyperphagic obesity. The associated impairment in memory, learning and nociception seen in the proband reflects the crucial role of TrkB in the human nervous system.
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                Author and article information

                Journal
                Int J Neuropsychopharmacol
                Int. J. Neuropsychopharmacol
                ijnp
                ijnp
                International Journal of Neuropsychopharmacology
                Oxford University Press (US )
                1461-1457
                1469-5111
                March 2015
                29 January 2015
                : 18
                : 5
                : pyu092
                Affiliations
                Department of Molecular Psychiatry, University Hospital of Psychiatry, University of Bern , Switzerland (Drs Homan and Hasler);
                Department of Psychiatry and Psychotherapy, University Hospital , Zurich, Switzerland (Dr Grob, Drs Milos and Schnyder);
                Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics Basel , Switzerland (Dr Eckert);
                Psychiatric University Clinics Basel , Switzerland (Dr Lang).
                Author notes
                Correspondence: Philipp Homan, MD, PhD, Department of Molecular Psychiatry, University Hospital of Psychiatry, University of Bern, Bolligenstrasse 111, 3000 Bern, Switzerland ( homan@ 123456puk.unibe.ch ).
                Article
                10.1093/ijnp/pyu092
                4376547
                25522424
                bbda84cc-37d7-4250-81b6-8b84ce2ad0bb
                © The Author 2015. Published by Oxford University Press on behalf of CINP.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 8 August 2014
                : 30 October 2014
                Page count
                Pages: 8
                Categories
                Research Article

                Pharmacology & Pharmaceutical medicine
                bdnf,leptin,reward,catecholamines,bulimia nervosa,alpha-methyl-para-tyrosine

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