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Abstract

Objective:

Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors.

Method:

Knock-in mice containing a common human single-nucleotide polymorphism (Val66Met; rs6265) in brain-derived neurotrophic factor (BDNF), a growth factor implicated in the mechanism of action of SSRIs, were studied based on their established phenotype of increased anxiety-like behavior. Timed administration of fluoxetine was delivered during one of three developmental periods (postnatal days 21–42, 40–61, or 60–81), spanning the transition from childhood to adulthood. Neurochemical and anxiety-like behavioral analyses were performed.

Results:

We identified a “sensitive period” during periadolescence (postnatal days 21–42) in which developmentally timed fluoxetine administration rescued anxiety-like phenotypes in BDNF Val66Met mice in adulthood. Compared with littermate controls, BDNFMet/Met mice exhibited diminished maturation of serotonergic fibers projecting particularly to the prefrontal cortex, as well as decreased expression of the serotonergic trophic factor S100B in the dorsal raphe. Interestingly, deficient serotonergic innervation, as well as S100B levels, were rescued with fluoxetine administration during periadolescence.

Conclusions:

These findings suggest that SSRI administration during a “sensitive period” during periadolescence leads to long-lasting anxiolytic effects in a genetic mouse model of elevated anxiety-like behaviors. These persistent effects highlight the role of BDNF in the maturation of the serotonin system and the capacity to enhance its development through a pharmacological intervention.

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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
Pages: 1203 - 1213
PubMed: 29084453

History

Received: 22 December 2015
Revision received: 1 May 2017
Revision received: 8 July 2017
Accepted: 14 July 2017
Published online: 31 October 2017
Published in print: December 01, 2017

Keywords

  1. Antidepressants
  2. Anxiety Disorder-Generalized
  3. Development
  4. BDNF

Authors

Details

Iva Dincheva, Ph.D.
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
Jianmin Yang, Ph.D.
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
Anfei Li, B.S.
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
Tina Marinic, B.A.
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
Helena Freilingsdorf, M.D.
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
Chienchun Huang, B.S.
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
B.J. Casey, Ph.D.
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
Barbara Hempstead, M.D., Ph.D.
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
Charles E. Glatt, M.D., Ph.D.
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
Francis S. Lee, M.D., Ph.D. [email protected]
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
Kevin G. Bath, Ph.D. [email protected]
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
Deqiang Jing, M.D., Ph.D. [email protected]
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.

Notes

Address correspondence to Dr. Jing ([email protected]), Dr. Bath ([email protected]), and Dr. Lee ([email protected]).

Author Contributions

The first two authors contributed equally to this work.

Competing Interests

Dr. Hempstead has received travel funds from UCB and served on a scientific advisory panel for Janssen, and her laboratory receives funding from UCB. The other authors report no financial relationships with commercial interests.

Funding Information

NewYork-Presbyterian Youth Anxiety Centre
Pritzker Neuropsychiatric Disorders Research Consortium
National Institutes of Health10.13039/100000002: MH079513, NS052819
Brain and Behavior Research Foundation10.13039/100000874
DeWitt-Wallace Fund of the New York Community Trust
Supported by NIH grants MH079513 (Dr. Casey, Dr. Lee, and Dr. Glatt) and NS052819 (Dr. Lee), the Pritzker Neuropsychiatric Disorders Research Consortium (Dr. Lee and Dr. Glatt), the New York–Presbyterian Youth Anxiety Center (Dr. Lee and Dr. Casey), the Brain and Behavior Research Foundation (Dr. Lee and Dr. Jing), the DeWitt-Wallace Fund of the New York Community Trust (Dr. Casey, Dr. Lee, and Dr. Glatt), and a generous gift by the Dr. Mortimer D. Sackler family.

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