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      The BDNF Val68Met polymorphism causes a sex specific alcohol preference over social interaction and also acute tolerance to the anxiolytic effects of alcohol, a phenotype driven by malfunction of BDNF in the ventral hippocampus of male mice


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          The brain-derived neurotrophic factor (BDNF) Valine 66 to Methionine human polymorphism results in impaired activity-dependent BDNF release and has been linked to psychiatric disorders including depression and anxiety. We previously showed that male knock-in mice carrying the mouse Methionine homolog (Met68BDNF) exhibit excessive and compulsive alcohol drinking behaviors as compared to the wild-type Val68BDNF mice.


          Here, we set out to determine the potential mechanism for the heightened and compulsive alcohol drinking phenotypes detected in Met68BDNF mice.


          We found that male, but not female Met68BDNF mice exhibit social anxiety-like behaviors. We further show that male Met68BDNF mice exhibit a preference for alcohol over social interaction. In contrast, alcohol place preference without an alternative social reward, is similar in male Met68BDNF and Val68BDNF mice. Since the Met68BDNF mice show social anxiety phenotypes, we tested whether alcohol reliefs anxiety similarly in Met68BDNF and Val68BDNF mice and found that male, but not female Met68BDNF mice are insensitive to the acute anxiolytic action of alcohol. Finally, we show that this acute tolerance to alcohol-dependent anxiolysis can be restored by overexpressing wild-type Val68BDNF in the ventral hippocampus (vHC) of Met68BDNF mice.


          Together, our results suggest that excessive alcohol drinking in the Met68BDNF may be attributed, in part, to heighted social anxiety and a lack of alcohol-dependent anxiolysis, a phenotype that is associated with malfunction of BDNF signaling in the vHC of male Met68BDNF mice.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s00213-022-06305-3.

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          Most cited references68

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          The use of the elevated plus maze as an assay of anxiety-related behavior in rodents.

          The elevated plus maze is a widely used behavioral assay for rodents and it has been validated to assess the anti-anxiety effects of pharmacological agents and steroid hormones, and to define brain regions and mechanisms underlying anxiety-related behavior. Briefly, rats or mice are placed at the junction of the four arms of the maze, facing an open arm, and entries/duration in each arm are recorded by a video-tracking system and observer simultaneously for 5 min. Other ethological parameters (i.e., rears, head dips and stretched-attend postures) can also be observed. An increase in open arm activity (duration and/or entries) reflects anti-anxiety behavior. In our laboratory, rats or mice are exposed to the plus maze on one occasion; thus, results can be obtained in 5 min per rodent.
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            The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence.

            Recent clinical observations and psychiatric diagnostic findings of drug-dependent individuals suggest that they are predisposed to addiction because they suffer with painful affect states and related psychiatric disorders. The drugs that addicts select are not chosen randomly. Their drug of choice is the result of an interaction between the psychopharmacologic action of the drug and the dominant painful feelings with which they struggle. Narcotic addicts prefer opiates because of their powerful muting action on the disorganizing and threatening affects of rage and aggression. Cocaine has its appeal because of its ability to relieve distress associated with depression, hypomania, and hyperactivity.
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              Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus.

              The dentate gyrus (DG), in addition to its role in learning and memory, is increasingly implicated in the pathophysiology of anxiety disorders. Here, we show that, dependent on their position along the dorsoventral axis of the hippocampus, DG granule cells (GCs) control specific features of anxiety and contextual learning. Using optogenetic techniques to either elevate or decrease GC activity, we demonstrate that GCs in the dorsal DG control exploratory drive and encoding, not retrieval, of contextual fear memories. In contrast, elevating the activity of GCs in the ventral DG has no effect on contextual learning but powerfully suppresses innate anxiety. These results suggest that strategies aimed at modulating the excitability of the ventral DG may be beneficial for the treatment of anxiety disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

                Author and article information

                Psychopharmacology (Berl)
                Psychopharmacology (Berl)
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                9 January 2023
                9 January 2023
                : 240
                : 2
                : 303-317
                GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Neurology, , University of California, ; 675 Nelson Rising Lane, BOX 0663, San Francisco, CA 94143-0663 USA
                © The Author(s) 2023

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Funded by: NIAAA
                Award ID: R37AA01684
                Award Recipient :
                Funded by: NIH
                Award ID: F32AA028422
                Award Recipient :
                Original Investigation
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                © Springer-Verlag GmbH Germany, part of Springer Nature 2023

                Pharmacology & Pharmaceutical medicine
                bdnf,bdnf val/met polymorphism,ventral hippocampus,alcohol


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