Thesis Rests with Its Author

University of Bath PHD Effect of antidepressant treatment on social behaviour and circadian rhythms of locomotor activity in the rat Mitchell, P. J. Award date: 1989 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 10. Oct. 2021 EFFECT OF ANTIDEPRESSANT TREATMENT ON SOCIAL BEHAVIOUR AND CIRCADIAN RHYTHMS OF LOCOMOTOR ACTIVITY IN THE RAT Submitted by P.J.Mitchell B.Sc., CBiol., MIBiol. for the degree of Doctor of Philosophy of the University of Bath 1989 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the prior written consent of the author. This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purposes of consultation. UMI Number: U013152 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U013152 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 UNIVEB? ' GA'H _ _ _ _ _ Lli. ' L ' l ____ 2 3 T l 6 OC T 1989 To Dad ACKNOWLEDGEMENTS I would like to express my thanks to Dr. P.H. Redfern for his continual help, encouragement and supervision he provided throughout this project. I would also like to thank Professor R.J. Flower for providing the use of the facilities of the School of Pharmacy and Pharmacology. My thanks to Mrs. M. Norris and her staff of the University of Bath animal house (especially Ewen, Lesley and Mike) for all their help and patience, and to Professor B. Silverman and Dr. P. Christie for their invaluable help on statistical analysis and the use of microcomputers respectively. I would like to express my thanks to my former colleagues and friends at Harlow, Essex, for their encouragement since I started this work, especially Dr. Frank Brown, John Clapham, and Alan Rainbird. My thanks also to Lyn and Peter for the use of their Laser printer. Lastly, my eternal gratitude to my mother and brother for their limitless support, encouragement and love that they have shown throughout my career, and to my fiancee Angie for her love and understanding. Without you this work would not have been possible and a promise never fulfilled. CONTENTS Page ACKNOWLEDGEMENTS i CONTENTS i i SUMMARY xi CHAPTER 1 CLINICAL AND PHARMACOLOGICAL PERSPECTIVES OF AFFECTIVE DISORDERS - DEPRESSION 1 1.1 Introduction 1 1.2 The Affective Disorders - Depression 1 1.2.1 Def inition 1 1.2.2 Classification 2 1.2.3 Epidemiology of Depression 5 1.2.4 Symptomology and Diagnosis of Depression 6 1.2.4.1 Symptomology 6 1.2.4.2 Diagnosis and Rating Scales 8 1.3 Neurotransmitter Abnormalities in Depression 11 1.3.1 Historical Perspectives 11 1.3.2 Neurotransmitter Abnormalities 13 1.3.2.1 The Serotonin System 13 1.3.2.2 The Noradrenaline System 17 1.3.3 Endocrine Abnormalities in Depression 19 1.4 Treatment of Depression 23 1.4.1 Historical Aspects 23 1.4.2 Monoamine Oxidase Inhibitors 24 1.4.2.1 Monoamine Oxidase 24 1.4.2.2 Inhibitors of Monoamine Oxidase 25 1.4.2.3 Inhibitors of Monoamine Oxidase and Monoamine Precursors 29 1.4.3 Monoamine Re-Uptake Inhibitors 31 1.4.3.1 5-HT and NA Re-uptake Processes 31 i i Page 1.4.3.2 Inhibitors of 5-HT and NA Re-uptake Processes 34 1.4.4 Atypical Antidepressants 39 1.4.5 Biochemical changes following chronic antidepressant treatment 41 1.5 Circadian Rhythms and Depression 55 1.5.1 Introduction 55 1.5.2 Circadian Rhythms 56 1.5.3 Circadian Rhythm Abnormalities and Depression 64 1.5.4 Antidepressants and Circadian Rhythms in Animal Studies 69 1.6 Hypotheses on the Aetiology of Depression 72 1.6.1 The Classical Monoamine Hypothesis 72 1.6.2 The Alternative Monoamine Hypothesis 73 1.6.3 The Circadian Rhythm Phase-Advance Hypothesis 74 1.7 Identification of Potential Antidepressants 75 1.7.1 Animal Models of Depression 75 1.7.2 Biochemical Methods 80 1.7.3 Comments 83 1.8 Conclusions 84 CHAPTER 2 AIMS OF THIS STUDY 87 CHAPTER 3 OVERVIEW OF THE RATIONALE OF EXPERIMENTAL PROTOCOLS 89 3.1 Social behaviour 89 3.2 Circadian locomotor activity 91 3.3 Choice of drugs 92 3.3.1 Clomipramine 94 3.3.2 Fluoxetine 95 3.3.3 Iprindole 97 3.3.4 Mianserin 98 3.3.5 Phenelzine 101 i i i Page 3.4 Doses 102 3.4.1 Social behaviour 102 3.4.2 Circadian locomotor activity 103 CHAPTER 4 MATERIALS 104 4.1 Animals 104 4.2 Lighting conditions 104 4.3 Environmental cabinets 105 4.3.1 Circadian locomotor activity of individual rats and rank order studies 106 4.3.2 Circadian locomotor activity of grouped rats 106 4.4 Recording apparatus 109 4.4.1 Social behaviour 109 4.4.1.1 Recording cabinet 110 4.4.1.2 Video camera and recorder 110 4.4.2 Circadian and exploratory locomotor activity 112 4.4.2.1 Practical considerations 112 4.4.2.2 Circadian locomotor activity of individual rats 112 4.4.2.3 Circadian locomotor activity of grouped rats and exploratory locomotor activity of individual rats 114 4.4.2.4 Infrared photocell units and computer hardware and software 116 4.5 Preparation and implantation/removal of osmotic mini-pumps 117 4.5.1 Implantation 118 4.5.2 Removal 118 4.6 Drugs and chemicals 119 Chapter 5 Social Interaction Studies In The Rat. 123 5.1 Introduction 123 5.1.1 Behavioural postures of rodent social behaviour 123 i v Page 5.2 Methods 127 5.2.1 Experimental Design 127 5.2.1.1 Methodological considerations 127 5.2.1.2 Subjects 131 5.2.2 Basic Methodology 131 5.2.2.1 Analysis Of Intruder-Alone Behaviours 132 5.2.2.2 Effect of acute drug treatment of the resident rat 132 5.2.2.3 Effect of chronic drug or drug-vehicle treatment of the resident rat 133 5.3 Identification and capture of rodent social behaviour 135 5.3.1 Video analysis 136 5.3.2 Capture of behavioural data 136 5.4 Statistical Analysis 137 5.4.1 Comparison of behavioural profiles exhibited by resident and intruder rats during social interaction 137 5.4.2 Effect of acute or chronic drug treatment on the behavioural profile exhibited by resident and non-drugged intruder rats during social interaction 137 5.5 Results 139 5.5.1 Preliminary behavioural studies 139 5.5.1.1 Behavioural profiles of resident and intruder rats exhibited during social interaction 139 5.5.1.1.1 Resident animals 139 5.5.1.1.2 Intruder animals 139 5.5.1.2 Intruder-alone behaviours 141 5.5.2 Effect of acute drug treatment on the social interaction behavioural profiles of resident and non-drugged intruder rats 141 5.5.2.1 Clomipramine 141 5.5.2.1.1 Resident animals 141 5.5.2.1.2 Intruder animals 143 v Page 5.5.2.2 Fluoxetine 146 5.5.2.2.1 Resident animals 146 5.5.2.2.2 Intruder animals 146 5.5.2.3 Iprindole 149 5.5.2.3.1 Resident animals 149 5.5.2.3.2 Intruder animals 149 5.5.2.4 Mianserin 152 5.5.2.4.1 Resident animals 152 5.5.2.4.2 Intruder animals 152 5.5.2.5 Phenelzine 155 5.5.2.5.1 Resident animals 155 5.5.2.5.2 Intruder animals 155 5.5.2.6 Haloperidol 158 5.5.2.6.1 Resident animals 158 5.5.2.6.2 Intruder animals 158 5.5.2.7 Diazepam 161 5.5.2.7.1 Resident animals 161 5.5.2.7.2 Intruder animals 161 5.5.3 Effect of chronic (14 day) drug or vehicle treatment on the social interaction behaviour of v resident and non-drugged intruder rats 165 5.5.3.1 H20 165 5.5.3.1.1 Resident animals 165 5.5.3.1.2 Intruder animals 166 5.5.3.2 Clomipramine 169 5.5.3.2.1 Resident animals 169 5.5.3.2.2 Intruder animals 170 5.5.3.3 Iprindole 173 5.5.3.3.1 Resident animals 173 5.5.3.3.2 Intruder animals 174 5.5.3.4 Mianserin 177 5.5.3.4.1 Resident animals 177 5.5.3.4.2 Intruder animals 178 5.5.3.5 Phenelzine 181 5.5.3.5.1 Resident animals 181 5.5.3.5.2 Intruder animals 182 5.5.3.6 Tartaric acid 185 5.5.3.6.1 Resident animals 185 5.5.3.6.2 Intruder animals 186 5.5.3.7 Fluoxetine 189 5.5.3.7.1 Resident animals 189 5.5.3.7.2 Intruder animals 190 vi Page 5.5.3.8 Haloperidol 193 5.5.3.8.1 Resident animals 193 5.5.3.8.2 Intruder animals 194 5.5.3.9 Diazepam Vehicle 197 5.5.3.9.1 Resident animals 197 5.5.3.9.2 Intruder animals 197 5.5.3.10 Diazepam 201 5.5.3.10.1 Resident animals 201 5.5.3.10.2 Intruder

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