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The Effect of 5-HT2C Receptor Activation on Nausea-Induced Behaviour in Rats

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The Effect of 5-HT2C Receptor Activation on Nausea-Induced Behaviour in Rats The Effect of 5-HT2C Receptor Activation on Nausea-Induced Behaviour in Rats by Leonardo Berardo Silenieks A Thesis presented to The University of Guelph In partial fulfilment of requirements for the degree of Master of Science in Biomedical Science (Neuroscience) Guelph, Ontario, Canada © Leonardo Berardo Silenieks, August, 2014 ABSTRACT THE EFFECT OF 5-HT2C RECEPTOR ACTIVATION ON NAUSEA-INDUCED BEHAVIOUR IN RATS Leonardo B Silenieks Advisor: University of Guelph, 2014 Professor Neil MacLusky Professor Linda A. Parker The present study aimed at investigating the role of the 5-HT2C receptor in nausea using different models of nausea-induced behaviour in rats. Two chemically distinct 5-HT2C agonists (lorcaserin and CP-809101) were evaluated using the conditioned gaping model. At therapeutically relevant doses, lorcaserin caused rats to display conditioned gaping reactions. This effect was successfully blocked by pre-treating the animals with the 5-HT2C antagonists SB-242084, suggesting that this receptor is involved in the genesis of nausea. In contrast, CP-809101 did not produce conditioned gaping in rats administered with doses higher than its efficacy range in feeding studies. These results suggest that the relevance of this receptor in nausea may be more complex than previously considered. It invites the question of whether functional selectivity may be the reason for the differences between side effect profiles of these two serotonergic drugs. iii Acknowledgements My master's thesis was only possible because of the support I've received along the way. I would like to formally thank my supervisor Dr. Linda Parker for not only giving me this opportunity, but also for being able to guide me through this project, from my research background through her area of expertise. Dr. Parker made my Masters experience an extremely valuable one through her insight, patience and ability to find ways to make it all possible. It was a pleasure to see her passion and dedication to scientific research and I know I will take some of that passion with me in my future endeavors. I am very grateful and feel privileged to have had her as my supervisor. I wish to thank my other supervisor, Dr. Neil MacLusky, for his input and contribution to my thesis. Through the last two years he has showed me that with hard work it really is possible to achieve my goals, and he allowed me to find and follow my own path. I would also like to thank Dr. Guy Higgins for seeing the potential in me and being my mentor for the last five years. His guidance has really helped me understand what my passions are and how to follow them. I would also like to thank Dr. Cheryl Limebeer for all her help, flexibility and technical expertise. There are few people that have such a large breadth of skills and knowledge combined with the will to teach them. I would also like to thank my fellow lab mates for making the Parker lab such a hospitable place, where help is available down the hallway at any time, especially Erin Rock and Martin Sticht for their help. I would also like to thank some of my other lab mates from my other lab, Winnie Lau, Amy Patrick and Sandy Thevarkunnel, for their friendship and willingness to help. I thank my dear wife and best friend, Carlin Sweeney, who has been my partner in so many ways in our last twelve years. I would not be able to accomplish so much without her wisdom, love, inspiration and stoicism. Without her, none of this would be possible. Lastly, I would like to thank my parents for their unending support throughout my life. They have inspired me to work hard and love science since I was young, and I know that I am only where I am because they helped me get here. I will simply never be able to thank them enough, so I dedicate this thesis to them. iv Table of Contents Abstract ........................................................................................................................................... ii Acknowledgements ........................................................................................................................ iii List of Abreviations ....................................................................................................................... vi List of Figures ............................................................................................................................... vii Chapter 1: General introduction...................................................................................................... 1 1.1 Nausea and emesis ........................................................................................................... 2 1.2 Serotonin and its role in nausea and emesis ..................................................................... 6 1.3 5-HT3 receptor .................................................................................................................. 7 1.4 5-HT1A receptor ................................................................................................................ 8 1.5 5-HT2 receptor .................................................................................................................. 9 1.6 Functional selectivity and serotonergic receptors .......................................................... 11 1.7 Models of emesis and nausea in the rat .......................................................................... 13 1.8 Conditioned flavour avoidance ...................................................................................... 15 1.9 Conditioned taste aversion and the taste reactivity test.................................................. 16 1.10 Pica ................................................................................................................................. 18 1.11 Present studies ................................................................................................................ 19 Chapter 2: Effects of 5-HT2C receptor agonists Lorcaserin and CP-809101 in the taste reactivity and conditioned flavour avoidance models in rats ........................................................................ 21 2.1 Introduction .................................................................................................................... 21 2.2 Methods .......................................................................................................................... 24 Animals and housing............................................................................................................. 24 Surgery .................................................................................................................................. 24 Apparatus .............................................................................................................................. 25 Drugs and treatment regimens .............................................................................................. 25 v Experiment 1 – Effect of lorcaserin in the test reactivity and flavour avoidance models .... 26 Experiment 2 – Effect of CP-809101 in the taste reactivity and flavour avoidance models 27 Experiment 3 - Effect of systemic SB-242084 pretreatment on Lorcaserin-induced conditioned gaping and flavour avoidance ........................................................................... 27 Data Analysis ........................................................................................................................ 28 2.3 Results ............................................................................................................................ 28 Experiment 1 – Effect of lorcaserin in the test reactivity and flavour avoidance models .... 28 Experiment 2 – Effect of CP-809101 in the taste reactivity and flavour avoidance models 29 Experiment 3 – Effect of systemic SB-242084 pretreatment on Lorcaserin-induced conditioned gaping and flavour avoidance ........................................................................... 31 2.4 Discussion ...................................................................................................................... 32 2.5 Conclusion ...................................................................................................................... 35 2.6 Figures ............................................................................................................................ 37 Chapter 3: Lorcaserin does not induce pica behaviour in rats ...................................................... 44 3.1 Introduction .................................................................................................................... 44 3.2 Materials and Methods ................................................................................................... 46 Animals and housing............................................................................................................. 46 Drugs and treatment regimens .............................................................................................. 46 Test conditions ...................................................................................................................... 47 Data analysis ......................................................................................................................... 47 3.3 Results ................................................................................................................................. 47 3.4 Discussion ..........................................................................................................................
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