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The Effect of Fluoxetine on Anxiety-Related Behaviours During Development

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The Effect of Fluoxetine on Anxiety-Related Behaviours During Development The effect of fluoxetine on anxiety-related behaviours during development Diana Chan A thesis in fulfilment of the requirements for the degrees of Doctor of Philosophy/Master of Psychology (Clinical) School of Psychology The University of New South Wales i Thesis/Dissertation Sheet Surname/Family Name : Chan Given Name/s : Diana Abbreviation for degree as give in the University calendar : PhD/M. Psych (Clinical) Faculty : Science School : Psychology Thesis Title : The effect of fluoxetine on anxiety-related behaviours during development Abstract 350 words maximum: (PLEASE TYPE) Selective serotonin reuptake inhibitors (SSRIs) are amongst the most commonly prescribed medications, and there is substantial evidence that they ameliorate symptoms of anxiety and depression. However, much of this research has been conducted in adults, and comparatively little is known about their risks and effectiveness at other ages. The experiments reported in this thesis contribute to addressing this knowledge gap by examining the effects of developmental exposure to fluoxetine (i.e., Prozac), which is one of the most frequently prescribed SSRIs, using a rat model. A significant number of infants are exposed to this drug during gestation or in the early postnatal period as up to 10% of mothers are prescribed SSRIs perinatally, and previous studies show that these drugs cross the placental barrier and are found in breast milk. The experiments described in Chapter 2 failed to find any consistent effects of early-life exposure to fluoxetine on the development of learned fear. Another set of experiments focused on adolescence, which is a peak period for the development of anxiety disorders. Critically, previous research has shown that adolescents are impaired at extinction, which forms the basis of exposure therapy, the gold-standard treatment for aberrant fear and worry. The experiments reported in Chapter 3 show that while fluoxetine improves extinction retention and reduces relapse in adult animals it does not have either effect in adolescents. The experiments reported in Chapter 4 further investigate this difference between adolescents and adults treated with fluoxetine by testing whether a similar pattern occurs on a context conditioning task. Again, the results supported a developmental dissociation in fluoxetine’s effects with it reducing context conditioning in adults but not adolescents. These experiments contribute to elucidating the consequences of fluoxetine treatment during different stages of development. Ultimately experiments such as these allow doctors and patients to more adequately weigh the risks of treatment against the potential benefits, which they cannot currently do because of the relative paucity of research in this area. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………………………………… ……………………………………..……………… ……….……………………...…….… Signature Witness Signature Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: i COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Table of contents Thesis/Dissertation sheet i Abstract vi Originality statement vii Acknowledgements ix Care and use of animals x List of figures xi List of abbreviations xiv Chapter 1: General Introduction 1 Antidepressants are commonly used to treat psychopathology. 1 SSRI treatments have good tolerability in clinical trials 3 SSRIs are effective for the treatment of anxiety 5 SSRIs are effective for the treatment of depression 7 How do SSRIs work? 9 Synaptic plasticity 11 Neurogenesis 13 Production of brain derived neurotrophic factor (BDNF) 16 Deciding whether to treat with SSRIs involves a cost-benefit analysis 18 SSRI use in pregnancy 18 SSRI use in adolescence 20 Chapter 2: The effect of early-life exposure to antidepressants on development 22 Methods 33 Experiment 2.1: The effect of postnatal fluoxetine exposure on shock 35 sensitivity Results and Discussion 36 Experiment 2.2: The effect of postnatal fluoxetine exposure on context 38 conditioning Results and Discussion 39 Experiment 2.3: The effect of postnatal fluoxetine exposure on long-term 41 memory Results and Discussion 42 ii Experiment 2.4: Association and non-associative contributions to 46 heightened levels of CS elicited freezing following fluoxetine exposure Results and Discussion 47 Experiment 2.5: Do fluoxetine-exposed infants show increased CS- 48 elicited freezing when tested after either 5 minutes or 24 hours? Results and Discussion 49 Experiment 2.6: Do fluoxetine-exposure infants show reduced CS-elicited 51 freezing 5 minutes after conditioning? Results and Discussion 52 Discussion 53 Learned vs unlearned fear tasks 55 Period of exposure 56 Type of SSRI 58 Age of the rats 59 Conclusion 60 Chapter 3: Adolescents and anxiety: Can antidepressants help? 62 Methods 73 Experiment 3.1: Does fluoxetine improve extinction retention in 76 adolescent rats? Results and Discussion 76 Experiment 3.2: Does fluoxetine reduce relapse after extinction in 79 adolescent rats? Results and Discussion 80 Experiment 3.3: Does fluoxetine have an effect on extinction retention 85 and reinstatement in adult rats? Results and Discussion 86 Experiment 3.4: Does fluoxetine exposure in adolescence impact its 91 effect in adulthood? Results and Discussion 93 Discussion 99 Developmental difference in pharmacokinetics as a possible 101 explanation of the findings Why does fluoxetine enhance extinction in the adult but not the 104 iii adolescent i) Limbic-prefrontal circuitry 105 ii) Brain derived neurotrophic factor (BDNF) 108 iii) Endocannabinoid system 110 Long-lasting consequences for exposure to fluoxetine during 112 development Chapter 4: Does fluoxetine’s effect on context conditioning differ between 115 adolescents and adults? Methods 120 Experiment 4.1: Replication demonstrating that fluoxetine-treated adult 122 rats exhibit reduced context conditioning Results and Discussion 122 Experiment 4.2: Does fluoxetine prevent context conditioning in adult 124 rats even when they are given two sessions of conditioning? Results and Discussion 124 Experiment 4.3: Does fluoxetine reduce context conditioning in 125 adolescent rats? Results and Discussion 125 Experiment 4.4: Does fluoxetine reduce context conditioning in 127 adolescents when a higher level of conditioning occurs in the control animals? Results and Discussion 127 Discussion 129 Reinstatement is closely linked to context conditioning 129 Other infant-like behaviour to consider in future research 130 Do the mechanisms proposed in Chapter 3 to explain the 132 developmental difference in fluoxetine’s effect on extinction also apply to context conditioning? Chapter 5: General Discussion 136 Section I: Fluoxetine causes adults to be infant-like 136 Adult rats treated with fluoxetine show infant-like behaviour 136 Reconsidering the mechanisms for infant-like behaviour in 137 fluoxetine-treated adults iv Fluoxetine induces infant-like plasticity in the visual cortex of 138 adult animals Fluoxetine shifts the PNNs of adult animals towards an immature 140 state Does fluoxetine reopen critical periods in the adolescents? 141 Section II: The interaction between fluoxetine and other medications 142 Interaction between antidepressants and DCS 142 Interaction between antidepressants and methylphenidate 146 Section III: Other issues to consider 152 Testing stressed vs non-stressed animals 152 Generalising the findings to females 155
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