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Neurobiological Consequences of Fluoxetine Exposure during Adolescence

Title: Neurobiological Consequences of Fluoxetine Exposure during Adolescence.
Name(s): Iñiguez, Sergio Diaz, author
Bolaños-Guzmán, Carlos A., professor directing dissertation
Gunjan, Akash, university representative
Wang, Zuoxin, committee member
Kabbaj, Mohamed, committee member
Kistner, Janet, committee member
Department of Psychology, degree granting department
Florida State University, degree granting institution
Type of Resource: text
Genre: Text
Issuance: monographic
Date Issued: 2011
Publisher: Florida State University
Place of Publication: Tallahassee, Florida
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Little is known regarding the mechanisms underlying the neurobiological consequences of antidepressant exposure during adolescence. Therefore, in this dissertation, I assessed the long-lasting effects of adolescent exposure to Fluoxetine (FLX), a selective serotonin reuptake inhibitor, on behavioral reactivity to emotion-eliciting stimuli in adulthood using rodent animal models. To do this, in chapters two and three, male Sprague-Dawley rats and c57BL/6 mice are exposed to FLX throughout adolescence (postnatal days 35-49), and tested in adulthood (postnatal day 70+) on a battery of behavioral tasks designed to assess sensitivity to stress- (i.e., forced swimming and the social defeat procedure), and anxiety-inducing situations (i.e., elevated plus-maze, novelty induced hypophagia, and open field test). Because a proposed mechanism by which FLX exerts its therapeutic effect(s) has been linked to the modulation of intracellular signaling pathways involved in the regulation of cell survival, in chapter three, I also assessed how FLX exposure influenced extracellular signal-regulated protein kinase 1/2 (ERK)-signaling within the ventral tegmental area (VTA) of the midbrain. The VTA was selected given the role this brain region plays in regulating mood and motivation under normal conditions. FLX exposure during adolescence resulted in an enduring paradoxical behavioral response in which rodents exhibit a stress-resistant behavioral phenotype, along an increase in sensitivity to anxiety-inducing situations. In addition, a persistent decrease in ERK-related signaling was observed within the VTA of rats and mice exposed to FLX. Given that chronic exposure to FLX resulted in an enduring downregulation of ERK signaling, it was imperative to determine whether exposure to stress, a major predisposing factor for depression, would result in oppositional regulation of this signaling pathway. Thus, in chapters three and four I assessed the behavioral and biochemical effects of exposure to stress in adult rats and mice using complementary behavioral, molecular, and gene transfer approaches. Here, exposure to chronic unpredictable stress resulted in depressive-like phenotypes, including a reduced ability to experience pleasure (i.e., anhedonia, as inferred from the sucrose preference test) and increased vulnerability to subsequent stress (i.e., forced swim test and the social defeat procedure). This stress-induced behavioral profile was also accompanied by an increase in ERK and its related signaling within the VTA - biochemical results opposite to those observed after FLX exposure. The functional significance of this oppositional effect was further confirmed using viral vectors: increasing ERK activity within the VTA increased sensitivity, whereas decreasing ERK resulted in decreased sensitivity to stress. Together, the data presented in this dissertation strongly implicate ERK signaling within the VTA as a modulator of behavioral responsivity to stress and antidepressant efficacy in adolescent and adult rodents. Lastly, in chapter five, the potential clinical implications, as well as future directions of this work are discussed.
Identifier: FSU_migr_etd-5718 (IID)
Submitted Note: A Dissertation submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Degree Awarded: Fall Semester, 2011.
Date of Defense: September 2, 2011.
Keywords: adolescence, anxiety, ERK, fluoxetine, major depression, ventral tegmental area
Bibliography Note: Includes bibliographical references.
Advisory Committee: Carlos A. Bolaños-Guzmán, Professor Directing Dissertation; Akash Gunjan, University Representative; Zuoxin Wang, Committee Member; Mohamed Kabbaj, Committee Member; Janet Kistner, Committee Member.
Subject(s): Psychology
Persistent Link to This Record:
Owner Institution: FSU

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Iñiguez, S. D. (2011). Neurobiological Consequences of Fluoxetine Exposure during Adolescence. Retrieved from