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The Neurophysiological, Behavioral and Cognitive Enhancing Effects of Adrafinil in the Aging Canine

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The Neurophysiological, Behavioral and Cognitive Enhancing Effects of Adrafinil in the Aging Canine The Neurophysiological, Behavioral and Cognitive Enhancing Effects of Adrafinil in the Aging Canine Heather M. Callahan A thesis submitted in conformity with the requirements for the degree of Masters of Science Graduate Department of Physiology University of Toronto O Copyright by Heather M. Callahan 2001 National Library Bibliothèque nationale du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 WeUingîon Street 395, nie Wellington Ottawa ON KIA ON4 Ottawa ON K1A ON4 Canada Canada The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant a la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or seil reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de rnicrofiche/film, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. 1. Abstract The Neurophysiological, Behaviord and Cognitive Enhancing Effects of Adrafiil in the Aging Canine Masters of Science, 200 1 Heather M. Callahan Department of Physiology?University of Toronto. Adratinil is a behavioral stimulant that is currently being used in France to prornote vigilance in the elderly. Most of our undentandinç of adrafinil cornes From it's main metabolite. modafinil. Although the exact mechanism of action of adratinil and modafini l is unknown. most of the research suggests that they are al- adrenergic agonists. When açed beagles were tested on the open field test following the administration of adratinil. the- showed an increase in total distance traveled without the presencr of stereotypical behaviors. On visual discrimination tasks. dogs adrninistered adrafinil made Fewer errors and required fcwer trials to reach a predetermined criterion than dogs given a placebo control. The EEG of dogs administered adratinil revealed a decrease in delta and theta activity and an increase in alpha and slow beta activity. Based on these findings, adrafinil provides excellent promise as a vigilance-prornotinç agent for aged dogs and the elderly human population. 2. Acknowledgernents In any endeavor. there is always a team of people who make it possible to accomplish the goal you set out to achieve. Since the earliest days of my graduate experience. 1 have had a number of people who stood by me, gave me advice, helped me out. loaned me money. cooked me food and even prevented me from having a very bad fall. I want to take this opportunity to thank al1 of them for making this an adventure 1 will never forget. Fiat of all. I would like to thank my parents, Kathleen Callahan and Wilson Smith. who went für beyond the requirements of parental love and suppon and who showed me what a real challenge was al1 about. Thank you to my siblings. Chns. Rosalind and Shawn. who have always been here for me and with whorn I share an unbreakable bond. Our path has not been easy but 1 am glad we share it together. To Nicos Pelavas. who was there from the beginning. thank you for showing me what real love looks like and for teaching me the phrase "bring it on little man". I would like to thank Patncia Atkinson. a great fnend and Iûb-mate. for putting beagles and friends ahead of sleep and sanity. To Antonio Mendonca (the great guru of ail things) for his excellent surgical skills. his teaching ability. his computer knowledge and mostly for his time and patience. Antonio. you are most definitely one of a kind. At the stan of graduate school. I didn't have much respect for cornputen, but Saman Sadeghi Hosseini and Blaine Condron (the computer guys) have taught me that real research isn't possible without one. I hope Sam never has to spend another Friday night in the Iab. Thank you to my thesis cornmittee: Hon Kwan. John MacDonald and Martin Wojtowicz. for having the patience to read this and offer your expen advice. 1 tmly believe that John MacDonald is partly responsible for this actually getting finished when he went above and beyond his job requirements as graduate watchdog. I would also like to thank a great collaborator. Elizabeth Head. Liz became a collaborator when she realized she loved the Sun in California more than the snow in Toronto. Liz was the one who introduced me to my very fint beagle and who taught me that dogs were not just large rats. Thank you Liz for your support. undentanding, patience, guidance and friendship over all of these yean. Finally. 1 would like to thank the tag team supervison Bill MacKay and Bill Milgram. Bill MacKay took a chance on me when 1 fint showed up on his doorstep and I hope he doesn't regret it. Bill. you have shown me that there is a great deal of integity within the scientific community and 1 truly hope our paths cross again in the future. Bill Milgnm is the person who has taught me so much about science and research. Bill. you've been a great inspiration to me and I'm very happy that you came into my life and gave me this wonderfui opportunity. 1 am also happy that on that first day when you asked me if 1 wanted to work with dogs. rats or humans. 1 chose the right species. For Beth Margolis. You came dong for the joumey and did not give up on me at my darkest moments. It is because of you that this made it to paper and 1 made it at A. 3.Table of Contents .. 1. ABSTRACT ..............................................................il ... 2. ACKNOWLEDGEMENTS ........................................... il1 3. DEDICATION .......................................................... v 3. TABLE OF CONTENTS ..............................................vi 5. LIST OF FIGURES ..................................................... ix 6 . LIST OF APPENDICES ...............................................xi .. 7. LIST OF ABBREVIATIONS ....................................... ..XI1 8. INTRODUCTION ...................................................... 1 8.1 CHEMICAL STRUCTURE .....................................1 8.2 MECHANIS M OF A C'Tm.................................... -3 8.2.1 The al -Adrerzergic Receptor Hvpotliesis ...................3 8.2.2 Effects of Orher Neiirotransmitters ..........................3 8.2.3 Orexirt as a New Mecliariisni of Action ......................4 6.3 NON-COGIVrTIVE BEHAVIOR ................................. 5 8.3.1 Operi Field Sporliurieoits Activity Test ........................ 5 8.3.2 Non-Cognitive Behuvior und Adrafinil .......................6 8.4 C0GNl'T.ION.......................................................... 6 8.1.1 Cognition in [lie Aging Canine .................................6 8.1.2 Cognition and Adrafinil ......................................... 7 8.5 EEG..................................................................... 8 8.5.1 The Origin of the Electroencephaiograni ..................... 8 8.12 nePhysiological Basis of the EEG ........................... 9 8.5.3 EEG urid Aging .................................................. 10 8.5.1 EEG and Canines ............................................... IO 8.5.5 EEG and Adrafiliil ............................................... 11 9.EXPEIWIENT 1: ADRAFINIL AS A BEHAVIORAL ACTIVATING AGENT IN AGING CANINES .......................15 9.2 MATERIALÇ AND METHODS ...................................... 15 9.2.1 Siibjccts ................................................................15 9.2.2 Beliavioraf Procedures ............................................. 16 9.2.3 Errperirnental Design ............................................... 16 9.2.3 Data Analysis ........................................................ 17 9.3 RESUL7S................................................................. 17 9.3.1 Eficts of Adrafiriil ori Locomotion ................................ 17 9.3.2 Effecrs of Aclrafiiil on Uririarion .................................. 20 9.3.3 Effects of Adrafilil or1 Vocaliratiori............................... 20 9.3.4 Effects of Adrufinil ori Aaivity Partem ..........................20 9.4 DISCUSSION ........................................................... -24 10.EXPERIMENT 2: ADRAFINIL AS A COGNITIVE ENHANCING AGENT IN AGING BEAGLE DOGS .................36 10.2 INTRODUCTION ...................................................... 26 1 O .2 MATERLALS AND METHODS .....................................36 10.2.1 Sicbjecrs ............................................................-26 10.2.2 Test Apparatus ..................................................... -26 10 .2.3 Pre- Traiuing Procediires .......................................... -28 10.2.1 Behaviorul Testing ................................................... 28 10.2.5 E.rper-imertra1 Design ................................................29 10.1.6 Data Amlysis ........................................................ 30 1 0.4 DISCUSSION ............................................................ 35 11.EXPERIMENT 3: THE EFFECTS OF ADRAFINIL ON EEG ACTIVITY IN AN AGED CALVINE:A PILOT STUDY ................................................. 37 11.2 MATERIALS AND ZbfElXOD....................................... 38 .uii . 11.2.1 Siibjects ..............................................................
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