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. / A Dissertation submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester, 2011. / September 2, 2011. / adolescence, anxiety, ERK, fluoxetine, major depression, ventral tegmental area / Includes bibliographical references. / Carlos A. Bolaños-Guzmán, Professor Directing Dissertation; Akash Gunjan, University Representative; Zuoxin Wang, Committee Member; Mohamed Kabbaj, Committee Member; Janet Kistner, Committee Member.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_183500 |
| Contributors | Iñiguez, Sergio Diaz (authoraut), 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) |
| Publisher | Florida State University, Florida State University |
| Source Sets | Florida State University |
| Language | English, English |
| Detected Language | English |
| Type | Text, text |
| Format | 1 online resource, computer, application/pdf |
| Rights | This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). The copyright in theses and dissertations completed at Florida State University is held by the students who author them. |
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