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Effects of Neonatal Clomipramine Treatment on Photic and Non-Photic Circadian Phase Shifting in Rats Suzanne M

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Effects of Neonatal Clomipramine Treatment on Photic and Non-Photic Circadian Phase Shifting in Rats Suzanne M The University of Maine DigitalCommons@UMaine Electronic Theses and Dissertations Fogler Library 12-2000 Effects of Neonatal Clomipramine Treatment on Photic and Non-Photic Circadian Phase Shifting in Rats Suzanne M. Dwyer Follow this and additional works at: http://digitalcommons.library.umaine.edu/etd Part of the Biological Psychology Commons Recommended Citation Dwyer, Suzanne M., "Effects of Neonatal Clomipramine Treatment on Photic and Non-Photic Circadian Phase Shifting in Rats" (2000). Electronic Theses and Dissertations. 283. http://digitalcommons.library.umaine.edu/etd/283 This Open-Access Dissertation is brought to you for free and open access by DigitalCommons@UMaine. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of DigitalCommons@UMaine. EFFECTS OF NEONATAL CLOMIPRAMINE TREATMENT ON PHOTIC AND NON-PHOTIC ClRCADlAN PHASE SHIFTING IN RATS Suzanne M. Dwyer B.Sc. Saint Mary’s University, 1993 Certificate of Honors Equivalency Saint Mary’s University, 1994 A THESIS Submitted in Partial fulfiltment of the Requirements for the Degree of Doctor of Philosophy On Ps~shelog~) The Graduate School The University of Maine December, 2009 Advisory Committee: Alan M. Rosenwasser, Professor of Psychology, Advisor Ziad Boulos, Research Scientist (New York State Psychiatric institute) Marie 3. Hayes, Associate Professor of Psychology Michael A. Robbins, Senior Research Associate and Cooperating Associate Professor of Psychology D. Alan Stubbs, Professor of Psychology EFFECTS OF NEONATAL CLOMIPRAMINE TREATMENT ON PHOTIC AND NON-PHOTIC CIRCADIAN PHASE SHIFTING IN RATS By Suzanne M. Dwyer Thesis Advisor: Dr. Alan M. Rosenwasser An Abstract of the Thesis Presented in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy (in Psychology) December, 2000 Neonatal exposure to monoaminergic antidepressant drugs produces a wide variety of effects on the behavior and physiology of adult rats which parallel those observed in human depression. Monoaminergic neurotransmitter systems are involved in the regulation of both affective and circadian behaviors, and alterations in circadian rhythmicity have been observed in depressed patients and in several other animal depression models. The purpose of the present study was to explore circadian phase shifting following neonatal antidepressant treatment. Neonatal rats were divided into three treatment groups; a clomipramine-treated group, a saline-treated group, and an unhandled group. Daily injections of clomipramine (25 mg/kg SC), a serotonin (5HT) re uptake inhibitor, or saline were given from postnatal day 8-21. The saline-treated group served as a control for the pharmacological effects of clomipramine, while the unhandled group was included to control for any stressors associated with the injection procedure. As adults, rats participated in one of two separate experiments designed to assess non- photic and photic phase shifting. In the non-photic experiment, stimuli included injections of 8-OH-DPAT (5mgIkg ip), a 5-HT agonist, and six-hour dark pulses, both of which were presented during subjective day. A significant difference was found between the clomipramine and saline-treated groups in both the size and direction of 8-OH-DPAT- induced phase shifts, as the clomipramine-treated group displayed a small phase advance while the saline-treated group showed a larger phase delay. Following dark pulses, all groups displayed mean phase advances, but no significant group differences were observed. For both 8-OH-DPAT and dark pulses however, the pattern of responses across the three neonatal groups indicates that neonatal clomipramine and saline treatment may have opposite effects on non-photic phase shifting. In the photic experiment, rats were presented with light pulses during early and late subjective night, but no significant group differences were found in the magnitude of the resulting phase shifts. Taken together, results of this study suggest that neonatal clomipramine treatment alters non-photic, but not photic phase shifting, and comparisons of the present results with those reported previously, provide support for species differences in the role of serotonin in circadian regulation. ACKNOWLEDGEMENTS I would like to express my appreciation to the members of my advisory committee -- Marie J. Hayes, Ph.D., 0. Alan Stubbs, Ph.D., Ziad Boulos, Ph.D., and Michael A. Robbins, Ph.D.-- for their contributions to this dissertation. A special thank you to my advisor, Alan M. Rosenwasser, Ph.D., for all his help and support over the course of my graduate school years. His lab was a fun and interesting place to work and learn about docks, and I truly value that experience. I would also like to express my deep gratitude to my parents, Brian and Anne Marie Dwyer. They have been a constant source of support and encouragement for me, without which I could not have completed this project, and I sincerely thank them. Alice Taylor and my brothers, Sean and Mark Dwyer, have been great friends to me, and I would also like to acknowledge them here. Finally, I would like to thank my fellow graduate students, particularly the Canadian contingent, for their support and friendship throughout this graduate school experience. III TABLE OF CONTENTS Acknowledgements ........................................................................................... ii List of Tables ...................................................................................................... vii List of Figures ..................................................................................................... x Chapter I. Introduction ....................................................................................... 1 Fundamental Properties of Circadian Rhythms ........................................ 1 Free-running Period ............................................................................. 1 Phase-Response Curves (PRCs) ........................................................ 2 Higher-Order Properties of Circadian Rhythms .......................................... 4 Entrainment ............................................................................................ 4 Constant Light (LL) ................................................................................. 6 Phase Shifting in Response to Behavioral Stimuli ........................................ 7 Interactions between Photic and Non-Photic Stimuli ................................... 10 Suprachiasmatic Nucleus (SCN) ................................................................... 12 Retinohypothalamic Tract (RHT) ................................................................... 15 lntergeniculate Leaflet (IGL)/Geniculohypothalamic Tract (GHT) ................ 17 Role of the IGUGHT in Photic Effects ................................................... 18 Role of the IGUGHT in Non-Photic Effects ........................................... 19 Role of the IGL/GHT in the Interaction between Photic and Non-Photic Effects................................................................................... 21 iv Raphe Nuclei/ Serotonin (5-HT) ............................................................................ 21 5-HT-Induced Phase Shifting .................................................................. 22 5-HT and Non-Photic Phase-Shifting ...................................................... 23 5-HT and Photic Phase-Shifting .............................................................. 25 SCN Output ............................................................................................................. 27 Circadian Dysfunction, Neurotransmitters and Depression ................................. 28 Cholinergic Effects on Circadian Rhythmicity.......................................... 31 Monoaminergic Effects on Circadian Rhythms ...................................... 32 Effects of Antidepressant Treatment on Circadian Rhythms: Animal Studies .... 33 Animal Models of Depression ................................................................................. 34 Flinders Sensitive (FSL) Rats .................................................................. 35 Olfactory Bulbectomy ............................................................................... 35 Chronic Stress .......................................................................................... 36 Developmental Models: Prenatal Stress ................................................ 37 Developmental Models: Neonatal Antidepressant Treatment .............. 38 Present Study ................................................................................................... 41 V Chapter II. Method ................................................................................................. 42 Subjects and Neonatal Treatment .................................................................. 42 Apparatus and Procedure ............................................................................... 45 Experiment 1: Effects of neonatal ciomipramine treatment on circadian phase shifting induced by dark pulses and serotonergic stimulation ......................................................................... 45 Experiment 2: Effects of neonatal ciomipramine treatment on circadian phase shifting induced by photic stimulation ......................... 46 Data Analysis ................................................................................................. 48 Chapter III. Results ...............................................................................................
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