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Published Online: 1 February 2011

Effect of 7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, on Emotional Learning

Raul Andero, Ph.D., Scott A. Heldt, Ph.D., Keqiang Ye, Ph.D., Xia Liu, B.S., Antonio Armario, Ph.D., and Kerry J. Ressler, M.D., Ph.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 168, Number 2
https://doi.org/10.1176/appi.ajp.2010.10030326
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Abstract

Objective:

Despite increasing awareness of the many important roles played by brain-derived neurotrophic factor (BDNF) activation of TrkB, a fuller understanding of this system and the use of potential TrkB-acting therapeutic agents has been limited by the lack of any identified small-molecule TrkB agonists that fully mimic the actions of BDNF at brain TrkB receptors in vivo. However, 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intraperitoneal administration. The authors combined pharmacological, biochemical, and behavioral approaches in a preclinical study examining the role of 7,8-DHF in modulating emotional memory in mice.

Method:

The authors first examined the ability of systemic 7,8-DHF to activate TrkB receptors in the amygdala. They then examined the effects of systemic 7,8-DHF on acquisition and extinction of conditioned fear, using specific and well-characterized BDNF-dependent learning paradigms in several models using naive mice and mice with prior traumatic stress exposure.

Results:

Amygdala TrkB receptors, which have previously been shown to be required for emotional learning, were activated by systemic 7,8-DHF (at 5 mg/kg i.p.). 7,8-DHF enhanced both the acquisition of fear and its extinction. It also appeared to rescue an extinction deficit in mice with a history of immobilization stress.

Conclusions:

These data suggest that 7,8-DHF may be an excellent agent for use in understanding the effects of TrkB activation in learning and memory paradigms and may be attractive for use in reversing learning and extinction deficits associated with psychopathology.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 168 • Number 2 • February 2011
Pages: 163 - 172
PubMed: 21123312

History

Received: 6 March 2010
Revision received: 8 July 2010
Revision received: 1 September 2010
Accepted: 13 September 2010
Published online: 1 February 2011
Published in print: February 2011

Authors

Details

Raul Andero, Ph.D.
From the Institute of Neurosciences, Animal Physiology Unit, Autonomous University of Barcelona, Spain; the University of Tennessee Health Science Center (Memphis); the Department of Pathology and Laboratory Medicine and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine; the Center for Behavioral Neuroscience, Yerkes National Primate Research Center, Emory University; and the Howard Hughes Medical Institute, Chevy Chase, Md.
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Scott A. Heldt, Ph.D.
From the Institute of Neurosciences, Animal Physiology Unit, Autonomous University of Barcelona, Spain; the University of Tennessee Health Science Center (Memphis); the Department of Pathology and Laboratory Medicine and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine; the Center for Behavioral Neuroscience, Yerkes National Primate Research Center, Emory University; and the Howard Hughes Medical Institute, Chevy Chase, Md.
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Keqiang Ye, Ph.D.
From the Institute of Neurosciences, Animal Physiology Unit, Autonomous University of Barcelona, Spain; the University of Tennessee Health Science Center (Memphis); the Department of Pathology and Laboratory Medicine and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine; the Center for Behavioral Neuroscience, Yerkes National Primate Research Center, Emory University; and the Howard Hughes Medical Institute, Chevy Chase, Md.
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Xia Liu, B.S.
From the Institute of Neurosciences, Animal Physiology Unit, Autonomous University of Barcelona, Spain; the University of Tennessee Health Science Center (Memphis); the Department of Pathology and Laboratory Medicine and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine; the Center for Behavioral Neuroscience, Yerkes National Primate Research Center, Emory University; and the Howard Hughes Medical Institute, Chevy Chase, Md.
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Antonio Armario, Ph.D.
From the Institute of Neurosciences, Animal Physiology Unit, Autonomous University of Barcelona, Spain; the University of Tennessee Health Science Center (Memphis); the Department of Pathology and Laboratory Medicine and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine; the Center for Behavioral Neuroscience, Yerkes National Primate Research Center, Emory University; and the Howard Hughes Medical Institute, Chevy Chase, Md.
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Kerry J. Ressler, M.D., Ph.D.
From the Institute of Neurosciences, Animal Physiology Unit, Autonomous University of Barcelona, Spain; the University of Tennessee Health Science Center (Memphis); the Department of Pathology and Laboratory Medicine and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine; the Center for Behavioral Neuroscience, Yerkes National Primate Research Center, Emory University; and the Howard Hughes Medical Institute, Chevy Chase, Md.
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Notes

Address correspondence and reprint requests to Dr. Ressler, Department of Psychiatry and Behavioral Sciences, Emory University, 954 Gatewood Dr., Atlanta, GA 30329; [email protected] (e-mail).

Funding Information

The authors report no financial relationships with commercial interests.Supported by NIH grant DA019624, National Science Foundation (NSF) grant GRFP DGE-0234618, the Center for Behavioral Neuroscience (NSF agreement IBN-987675), the Burroughs Wellcome Fund, and NIH/National Center for Research Resources base grant P51RR000165 to Yerkes National Primate Research Center. Support for Dr. Ye was also provided by NIH grant R01 NS045627. Support for Drs. Andero and Armario was also provided by Ministry of Science and Innovation (Madrid) grant SAF2008-01175, grant RD06/0001/0015 from the Instituto de Salud Carlos III, Redes temáticas de Investigación Cooperativa en Salud, and Ministry of Science and Innovation scholarship BES-2006-11901 (to Dr. Andero).

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