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Canada's University Run FACULTE DES ETUDES SUPERIEURES FACULTY of GRADUATE and ET POSTOCTORALES U Ottawa POSDOCTORAL STUDIES u Ottawa L'UniversiUi canadienne Canada's university run FACULTE DES ETUDES SUPERIEURES FACULTY OF GRADUATE AND ET POSTOCTORALES U Ottawa POSDOCTORAL STUDIES I.'University oanadierme Canada's university Noam Katz AUTEUR DE LA THESE / AUTHOR OF THESIS M.Sc. (Neuroscience) GRADE/DEGREE Department of Neuroscience FACULTE, ECOLE, DEPARTEMENT / FACULTY, SCHOOL, DEPARTMENT Effects of the Sustained Administration of the Catecholamine Reuptake Inhibitor Nomifensine on the Firing Activity of Norepinephrine, Dopamine and Serotonin Neurons TITRE DE LA THESE / TITLE OF THESIS Pierre Blier DIRECTEUR (DIRECTRICE) DE LA THESE/ THESIS SUPERVISOR CO-DIRECTEUR (CO-DIRECTRICE) DE LA THESE / THESIS CO-SUPERVISOR EXAMINATEURS (EXAMINATRICES) DE LA THESE/THESIS EXAMINERS Stefany Bennet .Gary.W. Slater Le Doyen de la Faculte des etudes superieures et postdoctorales / Dean of the Faculty of Graduate and Postdoctoral Studies Effects of the Sustained Administration of the Catecholamine Reuptake Inhibitor Nomifensine on the Firing Activity of Norepinephrine, Dopamine and Serotonin Neurons Noam Katz Department of Neuroscience Supervisor: Dr. Pierre Blier University of Ottawa This thesis is submitted to the Faculty of Graduate and Postdoctoral Studies as a partial fulfillment of the M.Sc. program in Neuroscience Noam Katz, Ottawa, Canada, 2008 1 Library and Bibliotheque et 1*1 Archives Canada Archives Canada Published Heritage Direction du Branch Patrimoine de I'edition 395 Wellington Street 395, rue Wellington Ottawa ON K1A0N4 Ottawa ON K1A0N4 Canada Canada Your file Votre reference ISBN: 978-0-494-46483-0 Our file Notre reference ISBN: 978-0-494-46483-0 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library permettant a la Bibliotheque et Archives and Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par Plntemet, prefer, telecommunication or on the Internet, distribuer et vendre des theses partout dans loan, distribute and sell theses le monde, a des fins commerciales ou autres, worldwide, for commercial or non­ sur support microforme, papier, electronique commercial purposes, in microform, et/ou autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in et des droits moraux qui protege cette these. this thesis. Neither the thesis Ni la these ni des extraits substantiels de nor substantial extracts from it celle-ci ne doivent etre imprimes ou autrement may be printed or otherwise reproduits sans son autorisation. reproduced without the author's permission. In compliance with the Canadian Conformement a la loi canadienne Privacy Act some supporting sur la protection de la vie privee, forms may have been removed quelques formulaires secondaires from this thesis. ont ete enleves de cette these. While these forms may be included Bien que ces formulaires in the document page count, aient inclus dans la pagination, their removal does not represent il n'y aura aucun contenu manquant. any loss of content from the thesis. Canada Abstract The effects of acute and sustained administration of the catecholamine reuptake inhibitor nomifensine were investigated on the firing properties of monoaminergic neurons in order to understand the mechanism of action of nomifensine in vivo. In vivo extracellular recordings of monoaminergic neurons were obtained from male Sprague-Dawley rats. Acute dose-response curves (i.v.) were constructed and subcutaneously implanted osmotic minipumps were used to investigate the effects of sustained administration. Nomifensine acted directly on both NE and DA neurons. Sustained administration potently inhibited DA neurons after 2 days, with a complete recovery after 14 days, due to D2 autoreceptor desensitization. NE neuronal firing rate was potently inhibited after 2 and 14 days of administration, while 5-HT neurons were increased at both times, partly due to 5-HTIA autoreceptor desensitization after 2 days. This medication likely treated depression by acting on DA, NE and 5-HT neurons, highlighting the importance of the functional connectivity between these systems. 11 ABSTRACT FIGURES ABBREVIATIONS ACKNOWLEDGMENTS INTRODUCTION 1. Major Depressive Disorder 2. Neuroanatomy 2.1. The Catecholamines 2.1.1. Neuroanatomy of the Norepinephrine System 2.1.1.1. Adrenergic Receptor Subtypes 2.1.1.1.1. a-Adrenergic Receptors 2.1.1.1.1.1. ar Adrenoceptors 2.1.1.1.1.2. a2-Adrenoceptors 2.1.1.1.1.3. p-Adrenoceptors 2.1.1.2. Electrophysiological Properties of NE Neurons 2.1.2. Neuroanatomy of the Dopamine System 2.1.2.1. Dopamine Receptor Subtypes 2.1.2.1.1. D2 Receptors 2.1.2.2. Electrophysiological properties of DA Neurons 2.1.3. Synthesis, Storage, Release and Metabolism of DA an 2.1.4. The NE and DA Transporters 2.2. The 5-Hydroxytryptamine System 2.2.1. Neuroanatomy of the 5-HT System 2.2.2. 5-HT Receptor Subtypes 2.2.2.1. 5-HTIA Receptors 2.2.3. 5-HT Synthesis, Storage, Release and Metabolism 2.2.4. The Serotonin Transporter (SERT) 2.2.5. Electrophysiological Properties of 5-HT Neurons 3. Evidence Implicating the Monoamines in the Pathophysiology of MDD 33 3.1. History of Antidepressants 33 3.2. Evidence of 5-HT Involvement in Depression 35 3.3. Evidence of Catecholamine Involvement in Depression 37 3.3.1. NE in Depression 37 3.3.2. DA in Depression 38 4. Reciprocal Interactions Between the Monaminergic Systems 39 4.1. NE - DA Interactions 39 4.2. 5-HT - NE Interactions 39 4.3. 5-HT - DA Interactions 41 4.4. Clinical Relevance of Interactions 42 5. Nomifensine - A Catacholamine Reuptake Inhibitor 44 5.1. Pharmacological Profile 44 5.2. Animal and Human Studies 45 MATERIALS AND METHODS 47 RESULTS 53 DISCUSSION 66 REFERENCES 75 iv Figures Introduction Figure 1: The major pathways of the 5-HT system Figure 2: Synthesis and metabolism of 5-HT Figure 3: The major pathways of the NE system Figure 4: The major pathways of the DA system Figure 5: Synthesis of the catecholamines DA and NE Figure 6: Major routes for the catabolism of DA Figure 7: Major routes for the catabolism of NE Figure 8: Functional interactions between monoaminergic neurons Figure 9: Chemical structure of nomifensine and sertraline Results Figure 10: Acute dose-response curves of i.v. administration of nomifensine in NE and DA neurons Figure 11: Average firing rate of DA neurons in the VTA Figure 12: Burst analyses of DA cells in the VTA Figure 13: Acute dose-response curve of DA autoreceptor sensitivity through i.v. administration of the DA agonist apomorphine Figure 14: Average firing rate of NE neurons Figure 15: Burst analysis of NE cells in the LC Figure 16: Average firing rate of 5-HT neurons in the DRN Figure 17: Burst analyses of 5-HT cells in the DRN Figure 18: Acute dose-response curve of the 5-HT autoreceptor sensitivity through i.v. administration of the 5-HTIA agonist LSD Figure 19: Measurement of whole blood 5-HT levels Figure 20: Effect of single- or dual-acting catecholaminergic reuptake inhibitors on escitalopram-induced decrease in DRN 5-HT neuronal activity v Abbreviations 5-HT - 5-hydroxytryptamine; serotonin 5-HTR - 5-HT receptors AR - adrenergic receptor CMS - chronic mild stress CNS - central nervous system COMT - catechol-O-methyl transferase DA - dopamine DAT - dopamine transporter DRN - dorsal raphe nucleus GPCR- G-protein coupled receptors ISI - interspike analysis KO - knockout LC - locus coeruleus MAO - monoamine oxidase MAOI - monoamine oxidase inhibitor MDD - major depressive disorder MFB - medial forebrain bundle MRN - median raphe nucleus NAcc - Nucleus Accumbens NE - norepinephrine NET - norepinephrine transporter NF - nomifensine NRI - norepinephrine reuptake inhibitor PCPA - para-chlorophenylalanine PLC - phospholipase C SERT - 5-HT transporter SN - substantia nigra TCA - tricyclic antidepressant TH — tyrosine hydroxylase TTX - tetrodotoxin VMAT - vesicular monoamine transporter VTA - ventral tegmental area vi Acknowledgments First and foremost I would like to thank my supervisor, Dr. Pierre Blier, not only for the incredible opportunity I have been afforded in being able to work in his laboratory for the past two years, but for the encouragement and guidance he has constantly provided along the way. I also wish to express my appreciation for each member that has been a part of my time at the IMHR, including lab-mates, office-mates and others, who all ensured that there was never a dull moment. A special thank you goes to Jonathan James for putting time and energy into helping analyze blood samples, and of course for his random stories. I would be remiss not to mention Dr. Gabriella Gobbi, who for the past three years has been heavily involved in my academic career, and has afforded me many opportunities during that time. It has all been greatly appreciated, and I know I would not be where I am today if it were not for her. There are far too many people who have been a major part of my life to mention here, but to all my friends who have been there along the way, both past and present, from western Canada to the Middle East, my most sincere thanks for being part of the journey. To SM and AF, two people with a very special place in my heart, thank you both for putting up with me, and for becoming such a big part of my life. You make life fun every single day, and it certainly would not be the same without you in it. Of course, I would in no way be the person I am today if it were not for my family. To Miriam, Jerry and Ari Katz, thank you for always believing in me and letting me know that no matter what, I will always have somewhere to turn in both the best and worst of times.
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