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Medial Prefrontal Cortex on Cardiac Chronotropic Reactivity

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Medial Prefrontal Cortex on Cardiac Chronotropic Reactivity INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the t»rt directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type o f computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely afreet reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note wiU indicate the deletion. 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UMI A Bell & Howell Information Company 300 North Zed) Road, Ann Arbor MI 48106-1346 USA 313/761-4700 800/521-0600 EFFECTS OF CHOLINERGIC MANIPULATIONS IN THE MEDIAL PREFRONTAL CORTEX ON CARDIAC CHRONOTROPIC REACTIVITY DISSERTATION Presented in Partial Fulfillment o f the Requirements for the Degree Doctor of Philosophy in the Graduate School o f The Ohio State University By Sheri Lyn Hart, B.S. ***** The Ohio State University 1998 Dissertation Committee: Approved by Gary G. Bemtson, Ph.D., Advisor Martin F. Sarter, Ph.D. I AdviAdvisor Cheryl M. Heesch, Ph.D. Neuroscience Graduate Program UMI Number: 9900840 Copyright 1999 by Hart, Sheri Lyn All rights reserved. UMI Microform 9900840 Copyright 1998, by UMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 ABSTRACT Consistent with its putative anxiogenic effects, the benzodiazepine receptor partial inverse agonist FG 7142 has previously been shown to enhance the defensive-like cardioacceleratory response to an acoustic probe stimulus. This FG-induced response potentiation appears to be mediated by a basal forebrain cholinergic mechanism. The present studies addressed the relevant projection sites o f the basal forebrain underlying this effect, and tested the hypothesis that the medial prefrontal cortex may be a critical target site. Results supported this hypothesis. Medial prefrontal, and not lateral prefrontal or basolateral amygdalar, carbachol infusions mimicked the response potentiating effects of FG 7142 administration. This effect was blocked by the muscarinic antagonist atropine. These findings suggest that cholinergic activation o f the medial prefrontal cortex is sufficient to enhance the cardioacceleratory defensive-like response. Additional studies further demonstrated that cholinergic blockade or cholinergic-specific lesions o f the medial prefrontal cortex can block the response potentiating effects o f FG. These findings indicate that a cholinergic mechanism o f the medial prefrontal cortex is necessary for the response potentiating effects o f FG. 11 ACKNOWLEDGMENTS I wish to foremost thank God for giving me the opportunity to better m yself with this pursuit. I also want to express my immeasurable thanks to my advisor. Dr. Gary Bemtson, who offered an exceptional academic role model, skillful tutelage and inexhaustible patience throughout my graduate studies. Drs. Martin F. Sarter and Cheryl M. Heesch are gratefully acknowledged for their interest in and guidance throughout this project. I would like to thank my colleague Janita Turchi for many productive conversations. To my parents, William and Evelyn Faber, I offer my most sincere thanks for their life-long unwavering confidence and loving support. I would like to express my gratitude to my brother, Gary, and his family, as well as to the rest o f my extended family, for their loving support. Finally, to my husband, Jeffery Hart, I would like to express my most sincere appreciation for his love, strength, humor, confidence and support, without which I would have been lost. Ill VITA July 4, 1969 ..................................................Bora- Binghamton, NY 1991 ............................................................... B.S. The Ohio State University 1991 - present................................................Researcher, The Ohio State University PUBLICATIONS Research Publication 1. Hart, S., Sarter, M., & Bemtson, G.G. (1998). Cardiovascular and somatic startle and defense: Concordant and discordant actions o f benzodiazepine receptor agonist and inverse agonists. Behavioural Brain Research, 90: 175-186. 2. Bemtson, G.G., Hart, S., & Sarter, M. (1997). The cardiovascular startle response: Anxiety and the benzodiazepine receptor complex. Psychophysiology, 34: 348- 357. 3. Bemtson, G.G., Hart, S., Ruland, S., & Sarter, M. (1996). A central cholinergic link in the cardiovascular effects o f the benzodiazepine receptor partial inverse agonist FG 7142. Behavioural Brain Research, 74: 91-103. 4. Quigley, K.S., Sarter, M.F., Hart, S.L., & Bemtson, G.G. (1994). Cardiovascular effect of the benzodiazepine receptor partial inverse agonist FG 7142 in rats. Behavioural Brain Research, 62: 11-20. FIELDS OF STUDY Major Field: Neuroscience IV TABLE OF CONTENTS Page Abstract .......................................................................................................................................... ii Acknowledgments .................................................................................................................... iii V ita ................................................................................................................................................. iv List of T a b les ...............................................................................................................................vii List of Figures ............................................................................................................................ ix Chapters: 1. Introduction 1.1. Cardiovascular reactivity and a n x iety ................................................................. I 1.2. Benzodiazepine receptor (BZR) ligands ...............................................................4 1.2.1. GABA^/BZ receptor pharmacology .......................................................4 1.2.2. BZR ligands and a n x iety ........................................................................... 6 1.2.3. Summary ...................................................................................................... 9 1.3. Basal forebrain - cortical cholinergic (BFCC) System ......................................9 1.3.1. BFCC anatomy ...................................................................................... 10 1.3.2. Acetylcholine and a n x iety .................................................................... 12 1.3.3. GABA/BZ - BFCC interactions ........................................................... 13 1.3.4. Summary ................................................................................................. 14 1.4. The medial prefrontal c o r te x .............................................................................. 15 1.4.1. General anatomy .................................................................................... 16 1.4.2. MPF and anxiety .................................................................................... 18 1.4.3. Modulation of MPF function by BZR ligands .....................................21 1.4.4. Summary .................................................................................................... 22 1.5. The am ygdala ............................................................................................................ 22 1.5.1. General anatomy .......................................................................................23 1.5.2. Amygdala and an x iety ..............................................................................25 1.5.3. Modulation of amygdalar function by BZR ligands ......................... 29 1.5.4. Summary .....................................................................................................30 1.6. General Summary ....................................................................................................30 2. General Methods 2.1. Surgical procedures ................................................................................................. 32 2.2. Physiologic recording .............................................................................................34 2.3. Testing procedures ....................................................................................................34 2.4. Pharmacologic agents .............................................................................................35 2.5. Histological analysis ............................................................................................... 35 2.6. General data reduction and analysis ......................................................................36 3. Effects o f infusions
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