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Loyola University Chicago Loyola eCommons Dissertations Theses and Dissertations 1988 Neurokinin Regulation of Midbrain Raphe Neurons: A Behavioral and Anatomical Study Joseph Paris Loyola University Chicago Follow this and additional works at: https://ecommons.luc.edu/luc_diss Part of the Medical Pharmacology Commons Recommended Citation Paris, Joseph, "Neurokinin Regulation of Midbrain Raphe Neurons: A Behavioral and Anatomical Study" (1988). Dissertations. 2519. https://ecommons.luc.edu/luc_diss/2519 This Dissertation is brought to you for free and open access by the Theses and Dissertations at Loyola eCommons. It has been accepted for inclusion in Dissertations by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. Copyright © 1988 Joseph Paris NEUROKININ REGUI.ATION OF MIDBRAIN RAPHE NEURONS: A BEHAVIORAL AND ANATOMICAL STUDY by Joseph M. Paris A Dissertation Submitted to the Faculty of the Graduate School of Loyola University of Chicago in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy July 1988 ACKNOWLEDGMENTS The pursuit of a graduate degree is an endeavor impossible to undertake alone. My parents and family provided the love and nurture which guided me to adulthood, and my wife, Nancy, furnishes the love and encouragement which make life possible. This dissertation, as well as the honors which I have received, are as much theirs as they are mine. I owe the shaping of my development as a scientist to the rein- forcement and counsel of my advisor, Dr. Stanley A. Lorens. He has taught me never to be satisfied with mediocrity. It has always been a privilege and honor to be regarded as his colleague and friend. I am indebted to: Marianne Guschwan, whose tireless viewing of videotapes made the open field studies possible; Dr. Hiroshi Mitsushio for his analysis of HPLC samples; and to Dr. Thackery Gray and Andrea Zardetto-Smith, of the Department of Anatomy, for the equipment and many helpful suggestions required during the anatomical studies. Special thanks go to Drs. John M. Lee and Clark Tedford who provided hours of fruitful dialogue. Lastly, I'd like to recognize the following people for their invaluable assistance and guidance during the course of my graduate education: Dr. Israel Hanin, Chairman, Department of Pharmacology; my dissertation committee, Drs. Nae Dun, T. Celeste Napier, E.J. Neafsey, and Lewis S. Seiden; Dr. Louis D. Van de Kar; the Arthur J. Schmitt Foundation; and the Deans and staff of the Graduate School, Drs. Fran­ cis J. Catania and Jill N. Reich, and Ms. Dee Miller and Patty Robert­ son. To those I inadvertently may have neglected to mention, I sin­ cerely apologize. ii VITA The author, Joseph Michael Paris, is the son of Samuel Angelo Paris and Theresa (Allotta) ~aris. Mr. Paris was born June 10, 1961, in Rochester, New York. In October, 1984, he was married to Nancy (Degnen) Paris of Glen Ellyn, Illinois. Mr. Paris' elementary education was obtained at Holy Apostles School, Rochester, New York. His secondary education was completed in 1979 at Loyola High School, Los Angeles, California. Mr. Paris entered the University of Southern California in Sep­ tember, 1979, and received the degree of Bachelor of Science in Biolog­ ical Sciences in June, 1983. While attending the University of South­ ern California in 1982, he began his research career as a Summer Fellow in the Department of Pathology at the University's Medical School. In July, 1983, Mr. Paris entered the graduate program of the Department of Pharmacology, Loyola University of Chicago, and achieved candidacy status in March, 1987. He was supported by a Searle Basic Science Fellowship from 1983 to 1987, and in May, 1987 was awarded a Dissertation Fellowship from the Arthur J. Schmitt Foundation. In September, 1987, Mr. Paris was honored with a Loyola University Presi- dent's Medallion for leadership, scholarship, and service. In May, 1988, he was inducted into Alpha Sigma Nu, the National Jesuit Honor Society. Mr. Paris is a student member of the American Society for Pharmacology and Experimental Therapeutics, and the Society for Neuro­ science, and an associate member of Sigma Xi, the graduate research honor society. iii TABLE OF CONTENTS Page ACKNOWLEDGMENTS ii VITA iii LIST OF TABLES ix LIST OF FIGURES ... x CONTENTS OF APPENDICES xi Chapter I. INTRODUCTION 1 II. REVIEW OF THE RELEVANT LITERATURE 9 A. Midbrain Raphe Nuclei 9 Co-localization of Transmitters within the Midbrain Rap he ............ 10 Co-localization with Substance P .. 11 Efferent Projections of the Midbrain Raphe 12 Afferent Connections of the Midbrain Raphe 13 Behavioral Effects of Midbrain Raphe Lesions 14 Pharmacological Manipulations of Midbrain Raphe Neurons . 16 Raphe 5-HT Neurons and Ingestive Behaviors 17 Raphe 5-HT Neurons and Anxiety 19 B. Neurokinins 20 Nomenclature . 21 Molecular Biology 21 Release . 23 Degradation 23 Neurokinin Antagonists 24 Localization Within the CNS 25 Binding Sites ...... 26 Peripheral Pharmacological Neurokinin Bioassays 27 Characterization of CNS Neurokinin Binding Sites 28 NK-2 Binding Sites in the CNS 29 Second-Messenger Coupling 30 Conformational Studies . 30 Distribution of CNS Neurokinin Binding Sites 31 Neurokinin Transmitter/Binding Site Mismatches 32 Recent Advances in Neurokinin Receptor Analysis 33 Electrophysiology . 34 Behavioral Effects of Neurokinins . 35 Behavioral Effects of Substance P Fragments 37 Avoidance Learning 38 iv TABLE OF CONTENTS (cont'd) Page Reinforcing Properties . 39 Spinally-Mediated Behavioral Effects 39 Sexual Behavior . 40 Neurokinin - S-HT Interactions in the CNS 40 Conclusions 42 III. METHODS ..... 44 A. Behavioral Studies 44 Animals .... 44 Cannula Implantation 44 Neurotoxin Lesions . 4S Apparatus .... 46 Handling and Habituation 47 Drug Testing . 48 Drugs . 49 Neurochemical Measurements Sl Sacrifice . S3 Histology . S3 Statistical Analysis S4 B. Anatomical Studies . S4 Animals . S4 Retrograde Tracing SS Iontophoresis SS Perfusion .. SS Tissue Sectioning and Processing S6 Immunocytochemistry S6 Colchicine Pretreatment S6 Perfusion . S7 Antisera S7 Tissue Sectioning and Processing S8 Microscopy S9 IV. RESULTS 60 A. Behavioral Studies Experiment I: DiMe-C7 Dose-Response Procedure 60 Results ........... 60 Experiment II: Non-Mammalian Tachykinin Dose­ Responses Procedure 64 Results . 64 v TABLE OF CONTENTS (cont'd) Page Experiment III: Mammalian Neurokinin Dose-Responses Procedure 68 Results . 68 Experiment IV: NKA Low Dose-Response Study Procedure 71 Results . 71 Experiment V: Senktide Low Dose-Response Study Procedure 73 Results .... 73 Regression Analysis 75 Experiment VI: Intra-MR NKB Injections Procedure 78 Results ............ 78 Experiment VII: 5,7-Dihydroxytryptamine (5,7-DHT) Lesions Procedure 80 Results . 80 Experiment VIII: DiMe-C7 Dose-Response in a Novel Open Field Procedure 87 Results . 87 Experiment IX: Neurokinin Effects on Novel Open Field Behavior Procedure 91 Results . 91 Experiment X: Neurokinin-Habituated Open Field Procedure .95 Results ............. 95 B. Anatomical Studies .... 100 Experiment I: Retrograde Tracing of MR Afferents 100 Telencephalon 100 Diencephalon 114 Mesencephalon 115 Metencephalon 116 Myelencephalon 117 Lower Medulla and Spinal Cord 117 vi TABLE OF CONTENTS (cont'd) Page Experiment II: Neurokinin Fiber Staining 118 Controls . 118 Experiment III: Neurokinin Perikarya Staining 123 Combined Fluoro-Gold and Neurokinin Immunocytochemistry 129 V. DISCUSSION 132 A. Behavioral Studies 133 Dose-Response Analysis of Intra-MR Neurokinin Infusions . 133 MR and Medial Forebrain Bundle 5,7-DHT Lesions 136 B. Anatomical Studies . 139 Cortical Afferents 142 Septal Afferents . 143 Basal Forebrain 143 Habenular Complex 144 Dorsal Thalamus 145 Zona Incerta . 145 Hypothalamus . 146 Substantia Nigra and Ventral Tegmental Area 147 Central Gray and Cuneiform Nucleus 147 Interpeduncular Nucleus 148 Gudden's Tegmental Nuclei . 148 Reticulotegmental Nucleus . 149 Pedunculopontine and Microcellular Tegmental Nuclei 149 Laterodorsal Tegmental Nucleus . 150 Raphe Nuclei . 150 Medial Nucleus of the Cerebellum 151 Visual System Afferents 151 Trigeminal Nuclei 152 Auditory Afferents . 152 Vestibular Inputs 153 Noradrenergic Afferents 153 Reticular Formation 154 C. Immunocytochemical Findings 154 Localization of Neurokinin-like Immunoreactivity in the Midbrain Raphe and Surrounding Regions 154 Problems Associated With Peptide Immunocyto- chemistry . 156 Neurokinin Immunoreactivity in Dorsal Root Ganglia 159 Localization of Neurokinin Cell Bodies in the CNS 160 vii TABLE OF CONTENTS (cont'd) Page Combined MR Fluoro-Gold Injections with Neurokinin Immunocytochemistry . 167 Future Considerations for Determining the Neurokinin Afferents to the MR . 168 D. Function of Neurokinin-Induced Hyperkinesis 169 What is the Function of Intra-MR Induced Hyperkinesis? . 170 Open Field Studies . 170 Punished Drinking . 172 Effects on Food and Water Intake 172 Effects on Reinforcement Processes and Pituitary-Adrenal Axis 173 Neurochemical Effects . 174 Neuroanatomical Considerations . 174 Mesencephalic Locomotor Region 175 Subthalamic Locomotor Region Connections . 176 Lateral Hypothalamic Locomotor Connections . 177 Association with the Mesotelen- cephalic DA Systems 178 Medial Frontal Cortical Projections and I.MA 179 Conclusions 180 SUMMARY 181 REFERENCES 185 APPENDIX I 238 APPENDIX II 260 viii LIST OF TABLES Table
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