PMID- 29084453 OWN - NLM STAT- MEDLINE DCOM- 20171219 LR - 20240213 IS - 1535-7228 (Electronic) IS - 0002-953X (Print) IS - 0002-953X (Linking) VI - 174 IP - 12 DP - 2017 Dec 1 TI - Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice. PG - 1203-1213 LID - 10.1176/appi.ajp.2017.15121592 [doi] AB - 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, BDNF(Met/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. FAU - Dincheva, Iva AU - Dincheva I AD - 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. FAU - Yang, Jianmin AU - Yang J AD - 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. FAU - Li, Anfei AU - Li A AD - 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. FAU - Marinic, Tina AU - Marinic T AD - 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. FAU - Freilingsdorf, Helena AU - Freilingsdorf H AD - 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. FAU - Huang, Chienchun AU - Huang C AD - 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. FAU - Casey, B J AU - Casey BJ AD - 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. FAU - Hempstead, Barbara AU - Hempstead B AD - 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. FAU - Glatt, Charles E AU - Glatt CE AD - 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. FAU - Lee, Francis S AU - Lee FS AD - 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. FAU - Bath, Kevin G AU - Bath KG AD - 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. FAU - Jing, Deqiang AU - Jing D AD - 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. LA - eng GR - P20 GM103430/GM/NIGMS NIH HHS/United States GR - P50 MH079513/MH/NIMH NIH HHS/United States GR - R01 NS052819/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20171031 PL - United States TA - Am J Psychiatry JT - The American journal of psychiatry JID - 0370512 RN - 0 (Anti-Anxiety Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (S100 Calcium Binding Protein beta Subunit) RN - 0 (S100b protein, mouse) RN - 0 (Serotonin Uptake Inhibitors) RN - 01K63SUP8D (Fluoxetine) SB - IM CIN - Am J Psychiatry. 2017 Dec 1;174(12 ):1137-1139. PMID: 29191031 MH - Age Factors MH - Animals MH - Anti-Anxiety Agents/*pharmacology/*therapeutic use MH - Anxiety/*drug therapy/*genetics MH - Brain-Derived Neurotrophic Factor/*genetics MH - Dorsal Raphe Nucleus/drug effects/metabolism MH - Eating/drug effects MH - Fear/drug effects MH - Fluoxetine/*pharmacology/*therapeutic use MH - Gene Knock-In Techniques MH - Male MH - Maze Learning/drug effects MH - Mice MH - Polymorphism, Single Nucleotide/genetics MH - Prefrontal Cortex/drug effects MH - S100 Calcium Binding Protein beta Subunit/metabolism MH - Serotonergic Neurons/drug effects MH - Selective Serotonin Reuptake Inhibitors/pharmacology/therapeutic use PMC - PMC5711544 MID - NIHMS900894 OTO - NOTNLM OT - Antidepressants OT - Anxiety Disorder-Generalized OT - BDNF OT - Development EDAT- 2017/11/01 06:00 MHDA- 2017/12/20 06:00 PMCR- 2018/12/01 CRDT- 2017/11/01 06:00 PHST- 2017/11/01 06:00 [pubmed] PHST- 2017/12/20 06:00 [medline] PHST- 2017/11/01 06:00 [entrez] PHST- 2018/12/01 00:00 [pmc-release] AID - 10.1176/appi.ajp.2017.15121592 [doi] PST - ppublish SO - Am J Psychiatry. 2017 Dec 1;174(12):1203-1213. doi: 10.1176/appi.ajp.2017.15121592. Epub 2017 Oct 31.