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Learning Under Stress: Separating the Effects of Allopregnanolone and Fluoxetine in Carassius Auratus

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Learning Under Stress: Separating the Effects of Allopregnanolone and Fluoxetine in Carassius Auratus LEARNING UNDER STRESS: SEPARATING THE EFFECTS OF ALLOPREGNANOLONE AND FLUOXETINE IN CARASSIUS AURATUS BY JEREMY DAVID EVANS A Thesis Submitted to the Division of Natural Sciences New College of Florida in partial fulfillment of the requirements for the degree Bachelor of Arts Under the sponsorship of Alfred Beulig, PhD Sarasota, Florida May, 2012 Dedication to Dinah, Devin, Donald: My caryatids. Foremost, to my goldfish. I'd a monument construe to the folks I knew but words are hardly true, frenetically flew from my mind the moment it was you anew. Lit like passions in somber passing stations, love like roses in spring-cessation: you may be mine to root attestations. ii Contents Dedication ........................................................................................................................................ ii Contents .......................................................................................................................................... iii Abstract ............................................................................................................................................ v Introduction ..................................................................................................................................... 1 Stress, the Endocrine System, and the Brain ............................................................................... 3 Defining Stress ......................................................................................................................... 3 Acute Allostatic Induction ........................................................................................................ 8 HPA/HPI Regulation and Dysregulation ................................................................................. 16 Cortisol in Humans and Fish ................................................................................................... 26 Allopregnanlone as a Mediator of the HPA/HPI .................................................................... 32 GABAA Receptors: Structure and Function ............................................................................ 34 Vertebrate Neurosteroids ...................................................................................................... 39 The Case for Telencephalic Homologies from Teleosts to Tetrapods ....................................... 52 Eversion vs. Evagination ......................................................................................................... 53 Teleostean Dorsal Pallium...................................................................................................... 56 Behavioral and Lesion Studies ............................................................................................... 59 Rationale for the Present Study ................................................................................................. 61 Hypotheses ............................................................................................................................ 62 Methods ......................................................................................................................................... 63 Subjects ...................................................................................................................................... 63 Husbandry and Aquaria ............................................................................................................. 64 Location ...................................................................................................................................... 65 Apparatus ................................................................................................................................... 65 Data Collection ........................................................................................................................... 66 Scototaxis ............................................................................................................................... 66 Delay Learning Task ............................................................................................................... 67 Trace Learning Task ................................................................................................................ 68 Experimental Design .................................................................................................................. 68 Treatment Preparation .......................................................................................................... 69 Results ............................................................................................................................................ 71 iii Scototaxis ................................................................................................................................... 71 Cognition .................................................................................................................................... 73 Delay Learning........................................................................................................................ 74 Trace Learning ........................................................................................................................ 81 Observations .............................................................................................................................. 88 Discussion ...................................................................................................................................... 89 Interpretations ........................................................................................................................... 91 Possible Confounds .................................................................................................................... 96 Depression and SSRI Efficacy ..................................................................................................... 97 References ................................................................................................................................... 103 APPENDIX I: .................................................................................................................................. 142 Additional Graphs and Tables .................................................................................................. 142 APPENDIX II: ................................................................................................................................. 150 Actinopterygii ....................................................................................................................... 150 Chondichthyes ..................................................................................................................... 152 Coelacanths .......................................................................................................................... 154 Anatomical and Hodological Models of Pallial Arrangemen ............................................... 157 Embryonic Origins of Pallial Zones ....................................................................................... 163 iv Abstract This thesis compares the cognitive and affective effects of two anxiolytic compounds in the gold- fish, Carassius auratus: fluoxetine (Prozac©), an antidepressant, and allopregnanolone, a neuro- steroid native to the brain of vertebrates. There is a literature review on the role of the interac- tions of stress, the endocrine system, and the brain in both goldfish and humans to stage the hypotheses in question, ultimately predicting a decline in cognition in fish exposed to the anxio- lytics unless they are also presented with exogenous stress. The results of the scototaxic trials indicate a significant increase in exploratory behavior in only the allopregnanolone group over the control. Cortisol-treated groups exhibited greater initial avoidance behavior, but this effect diminished in latter trials, resulting in significant impairments by the final block. Those fish treated with anxiolytics and cortisol presented a similar pattern, but with only allopregnano- lone+cortisol demonstrating hippocampal-dependent avoidance behavior on par with the con- trol group by the end of the experiment. Throughout the trials, all fish treated with fluoxetine demonstrated substantial impairments, especially in tests that required the retention of a trace stimulus. In conclusion: it is apparent that fluoxetine impedes temporal cognition in goldfish, even when compensating for hypercortisolemia, and that allopregnanolone is capable of ame- liorating the cognitive deficits imposed by chronic stress on the hippocampal homologue in gold- fish. Additionally, the acute anxiolytic effects of allopregnanolone are likely conserved in the goldfish. v Introduction Modern psychopharmaceutical therapies are notorious for their inefficacy relative to other medical treatments and often toxic side-effects (Leucht et al, 2012). Given that psychiatric disorders are generally only loosely correlated with biological findings and that the understand- ing of causality is still a distant goal, it is unsurprising that clinical psychiatry has not yet been realized as clinical neuroscience (Reynolds et al, 2009; Insel and Quirion, 2012; Kraemer, Schultz, and Arndt, 2002). Instead, positive results in clinical trials lead to the adoption of treatment par- adigms for complex disorders without a full understanding
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