Impact of depressogenic- and antidepressant-like challenges on monoamine system activities: in vivo electrophysiological characterization studies Chris A. Oosterhof Department of Cellular & Molecular Medicine University of Ottawa Thesis submitted in partial fulfillment of the requirements for the Doctor of Philosophy Degree in Neuroscience © Chris A. Oosterhof, Ottawa, Canada, 2016 Table of contents Table of contents ............................................................................................................. ii Acknowledgements ........................................................................................................ iv Statement of contributions .............................................................................................. v List of figures ................................................................................................................. vi List of tables .................................................................................................................. vii Glossary ........................................................................................................................ viii Abstract .......................................................................................................................... xi 1) Major depressive disorder ............................................................................................... 1 2) Monoamine systems........................................................................................................ 3 2.1 The 5-HT system ....................................................................................................... 3 2.1.1 5-HT: Synthesis, storage, release, and metabolism ............................................ 6 2.1.2 SERT .................................................................................................................. 9 2.1.3 5-HT receptors.................................................................................................. 10 2.1.3.1 5-HT 1A receptors ....................................................................................... 11 2.1.3.2 5-HT 1A autoreceptors ................................................................................ 11 2.1.3.3 Postsynaptic intrasynaptic 5-HT 1A receptors ............................................ 12 2.1.3.4 Postsynaptic extrasynaptic 5-HT 1A receptors ............................................ 13 2.1.3.5 5-HT 1B/D receptors ..................................................................................... 14 2.1.3.6 5-HT 2A receptors ....................................................................................... 15 2.1.3.7 5-HT 2B receptors ....................................................................................... 17 2.1.3.8 5-HT 2C receptors ....................................................................................... 17 2.1.4 Abnormalities in the 5-HT system; relevance to MDD ................................... 18 2.2 The norepinephrine system ..................................................................................... 21 2.2.1 NE: Synthesis, storage, release, and metabolism ............................................. 23 2.2.2 NET .................................................................................................................. 24 2.2.2 NET .................................................................................................................. 25 2.2.3 Adrenergic receptors ........................................................................................ 25 2.2.3.1 α 1-adrenergic receptors .............................................................................. 26 2.2.3.2 α 2-adrenergic receptors .............................................................................. 27 2.2.3.3 ß-adrenoceptors. ........................................................................................ 29 2.2.4 Abnormalities in the NE system; relevance to MDD ....................................... 30 2.3 The dopamine system .............................................................................................. 33 2.3.1 DA: Synthesis, storage, release, and metabolism............................................. 35 2.3.2 DA receptors .................................................................................................... 37 2.2.3 Abnormalities in the DA system; relevance to MDD ...................................... 39 2.4 Monoamine system interactions .............................................................................. 41 2.4.1.1 NE & 5-HT: presynaptic interactions............................................................ 42 2.4.1.1 NE & 5-HT: presynaptic interactions............................................................ 43 2.4.1.2 NE & 5-HT: postsynaptic interactions .......................................................... 45 2.4.2.1 5-HT & DA: presynaptic interactions ........................................................... 46 2.4.2.2 5-HT & DA: postsynaptic interactions.......................................................... 48 2.4.3 DA-NE interactions .......................................................................................... 48 2.5 Antidepressants & monoamine systems .................................................................. 51 2.5.1 Selective serotonin reuptake inhibitors ............................................................ 53 2.5.2 5-HT 1A receptor agonists .................................................................................. 55 ii 2.5.3 Norepinephrine reuptake inhibitors .................................................................. 56 2.5.4 Serotonin/norepinephrine reuptake inhibitors .................................................. 58 2.5.5 Tricyclic antidepressants .................................................................................. 60 2.5.6 Mirtazapine....................................................................................................... 62 2.5.7 Vortioxetine ...................................................................................................... 63 2.5.8 Bupropion ......................................................................................................... 64 2.5.9 Monoamine oxidase inhibitors ......................................................................... 65 2.5.10 Ketamine ........................................................................................................ 66 2.5.11 Atypical antipsychotics .................................................................................. 67 2.5.11.1 Dibenzepines ........................................................................................... 68 2.5.11.2 Benzisoxazoles ........................................................................................ 71 2.5.11.3 Aripiprazole ............................................................................................. 72 2.5.12 Augmentation strategies ................................................................................. 73 2.5.12.1 Mirtazapine augmentation ....................................................................... 73 2.5.12.2 Bupropion augmentation ......................................................................... 74 2.5.12.3 Quetiapine augmentation......................................................................... 75 2.5.12.4 Risperidone augmentation ....................................................................... 76 2.5.12.5 Aripiprazole augmentation ...................................................................... 76 2.5.13 Non-pharmacological interventions ............................................................... 77 2.5.13.1 Deep brain stimulation ............................................................................ 77 2.5.13.2 Vagus nerve stimulation .......................................................................... 79 2.5.13.3 Electroconvulsive therapy ....................................................................... 80 2.5.13.4 Sleep deprivation ..................................................................................... 80 2.5.14 Study rationale chapter I-III ........................................................................... 82 3) Stress and depression .................................................................................................... 85 3.1 What is stress? ......................................................................................................... 85 3.2 The HPA axis .......................................................................................................... 86 3.3 The HPA axis in MDD ............................................................................................ 87 3.4. Prenatal stress: an animal model for depression .................................................... 89 3.5 Study rationale chapter IV....................................................................................... 91 Chapter I: Sustained asenapine ......................................................................................... 93 Chapter II: Acute brexpiprazole ...................................................................................... 130 Chapter III: Sustained brexpiprazole ............................................................................... 167 Chapter IV: Prenatal stress .............................................................................................