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Neurobiological Bases of the Use of Atypical Antipsychotics in Treatment-Resistant Major Depressive Disorder

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Neurobiological Bases of the Use of Atypical Antipsychotics in Treatment-Resistant Major Depressive Disorder Neurobiological Bases of the use of Atypical Antipsychotics in Treatment-Resistant Major Depressive Disorder Julia Kirby University of Ottawa, Institute of Mental Health Research Faculty of Medicine Department of Neuroscience Ottawa, ON, Canada This thesis is submitted to the Faculty of Graduate and Postdoctoral studies as a partial fulfillment of the M.Sc. program in Neuroscience. Submitted on February 2, 2018 © Julia Kirby, Ottawa, Canada, 2018 ABSTRACT Only one third of depressed patients experience a beneficial therapeutic effect after using a first-line medication, leaving two-thirds of patients without effective treatment. It has been shown that a combination of two drugs with different modes of action result in an increase in the number of patients responding to treatment. One of the most effective strategies is the addition of low doses of an atypical antipsychotic. In- depth evaluation of the neurobiological properties of atypical antipsychotics have revealed that these agents produce antidepressant effects and enhance the therapeutic response of first-line medications through antagonism of the 5-HT2A, 5-HT2C, 5-HT1B/D, 5- HT7 receptors and NET; agonism of the 5-HT1A receptor; and/or D2/3 partial agonism. The present experiments focused on determining the mode of action of this combination of drugs to help design better antidepressant treatment in the future. A series of electrophysiological experiments were proposed to assess 5-HT and NE neurotransmission in the rat hippocampus, as well as DA transmission in the rat forebrain. ii Table of Contents ABSTRACT .................................................................................................................................... ii LIST OF FIGURES ....................................................................................................................... iv LIST OF ABBREVIATIONS ........................................................................................................ v ACKNOWLEDGEMENTS ......................................................................................................... vii CHAPTER 1: INTRODUCTION................................................................................................. 1 1.1 Major Depressive Disorder ............................................................................................... 1 1.1.1. Background ........................................................................................................................................... 1 1.2.2. Etiology ................................................................................................................................................... 2 1.2.3. Brain Systems Involved in Major Depressive Disorder ...................................................... 7 1.2.4. Scope of the Problem ........................................................................................................................ 8 1.2. Monoamine Systems .................................................................................................................. 8 1.2.1. Serotonin ............................................................................................................................................... 8 1.2.2. Dopamine ........................................................................................................................................... 19 1.2.3. Norepinephrine ................................................................................................................................ 26 1.3. Functional Interactions .......................................................................................................... 35 1.4. Treatment Strategies .............................................................................................................. 37 1.4.1. Non-Pharmacological .................................................................................................................... 37 1.4.2. Pharmacological .............................................................................................................................. 38 1.5. Rationale...................................................................................................................................... 43 CHAPTER 2: OBJECTIVES & HYPOTHESES ..................................................................... 49 CHAPTER 3: MATERIALS & METHODS ............................................................................ 50 3.1 Proposed Experiments ............................................................................................................ 50 3.1.1 Electrophysiological assessment of 5-HT neurotransmission in the rat hippocampus ................................................................................................................................................. 50 3.1.2 Assessment of NE neurotransmission in the rat hippocampus .................................... 50 3.1.3 Assessment of DA transmission in the rat forebrain ......................................................... 51 3.2 Treatments .................................................................................................................................. 51 3.3 Extracellular unitary recordings ......................................................................................... 51 3.4 Tool Compounds ........................................................................................................................ 52 3.5 Data Analysis ............................................................................................................................... 52 CHAPTER 5: DISCUSSION .................................................... Error! Bookmark not defined. 5.1 Results ......................................................................................... Error! Bookmark not defined. 5.2 Properties of atypical antipsychotics accounting for their use in treating major depressive disorder ......................................................................................................................... 56 5.2.1 5-HT2A Receptors .............................................................................................................................. 56 5.2.2 5-HT2C Receptors .............................................................................................................................. 57 5.2.3 α2-adrenergic Receptors and NET blockade ......................................................................... 58 5.2.4 5-HT1A Receptor Activation .......................................................................................................... 61 5.2.5 D2/3 Receptor Agonism ................................................................................................................... 62 5.2.6 5-HT1B/D Autoreceptors ................................................................................................................. 65 5.2.7 5-HT7 Receptors ................................................................................................................................ 66 REFERENCES ............................................................................................................................. 68 iii LIST OF FIGURES Figure 1. The Serotonin System Figure 2. The Dopamine System Figure 3. The Norepinephrine System Figure 4. Functional Connectivity of Monoaminergic Neurons Figure 5. Mean firing rate of DRN 5-HT neurons in control rats and rats treated with escitalopram or citalopram for 7, 14, and 21 days. Figure 6. Effects of 2 day administration of escitalopram on NE neuronal firing rate Figure 7. Effects of 14 day administration of citalopram and escitalopram on DA neuronal firing rate in the VTA Figure 8. Effects of aripiprazole administration on the firing activity of 5-HT neurons in the dorsal raphe Figure 9. Effects of acute administration of escitalopram, aripiprazole, and their combination on 5-HT spontaneous firing rate Figure 10. Effect of D2 antagonist PALI on 5-HT neuronal firing in control rats and rats treated with aripiprazole treated for 2 days. Figure 11. Firing rate of hippocampus CA3 pyramidal neurons in response to microiontophoretic application of 5-HT Figure 12. Assessment of tonic activation of 5-HT1A receptors in hippocampus CA3 pyramidal neurons Figure 13. RT50 values calculated from microiontophoretic application of 5-HT (20nA) in control, and rats treated with escitalopram for 2 and 14 days. iv LIST OF ABBREVIATIONS 5-HT 5-Hydroxytryptamine; serotonin 5-HTP 5-Hydroxytryptophan 7TM Seven transmembrane AADC Amino Acid Decarboxylase ACh Acetylcholine ARI Aripiprazole ACTH Adrenocorticotropic Hormone ATP Adenosine Triphosphate BDNF Brain-Derived Neurotrophic Factor cAMP Cyclic Adenosine Monophosphate CANMAT Canadian Network for Mood and Anxiety Treatments CBT Cognitive Behavioural Therapy CCK Cholecystokinin CNS Central Nervous System COMT Catechol-O-methyltransferase CPu Caudate Putamen CRH Corticotropin-Releasing Hormone CSF Cerebrospinal Fluid DA Dopamine DAT Dopamine Transporter DHMA 3,4-Dihydroxymandelic acid DHPG 3,4-Dihydroxyphenylglycol DNA Deoxyribonucleic acid DNB Dorsal Noradrenergic Bundle DOPA 3,4-Dihydroxyphenylalanine DRN Dorsal Raphe Nucleus ECF Extracellular fluid ESC Escitalopram FKBP5 FK506 Binding Protein 5 GABA Gamma-Aminobutyric Acid (γ-Aminobutyric acid) GPCR G-Protein Coupled Receptor GTP Guanosine-5'-triphosphate HPA Hypothalamic-Pituitary-Adrenal HVA Homovanillic Acid IFN-α Interferon-α
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