INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of 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 affect 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 will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. University Microfilms International A Bell & Howell Information Company 300 North Zeeb Road. Ann Arbor, Ml 48106-1346 USA 313/761-4700 800/521-0600 Order Number 9218993 Modulation of hyperactivity and reward by excitatory amino acid, serotonin, and opiate receptors in nucleus accumbens Layer, Richard Thomas, Ph.D. The Ohio State University, 1992 UMI 300 N. Zeeb Rd. Ann Arbor, MI 48106 MODULATION OF HYPERACTIVITY AND REWARD BY EXCITATORY AMINO ACID, SEROTONIN, AND OPIATE RECEPTORS IN NUCLEUS ACCUMBENS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Richard T. Layer, B.A., M.Sc. The Ohio State University 1992 Dissertation Committee: Approved by Dennis R. Feller, Ph.D Norman J. Uretsky, Ph.D Acjyisor Lane J. Wallace, Ph.D. College of Pharmacy The Secret Sits We dance round in a ring and suppose, But the Secret sits in the middle and knows. -Robert Frost To Lynda, my partner, who stoically endured both my rantings and ravings, and the chaotic appearance of our home while this dissertation was in preparation, and who loved me throughout. I couldn’t have done it without you. ACKNOWLEDGEMENTS I would like to thank my fellow students, past and present, comrades all. Together we shared the slings and arrows of outrageous fortune. I also would like to thank Bob Warwick, friend and advisor, from whom I learned the basics of pharmacology and banjo picking. I would like to express my appreciation to my committee, Dennis R. Feller, and especially Norman J. Uretsky. Your humor, guidance and advice were invaluable. I would like to especially thank my mentor, Lane J. Wallace, for his advice, insight, generosity, and friendship. You gave me the right combination of freedom and direction, and I am grateful. From you I have learned much, including, among other things, the beauty of a good fade away jump shot. Finally, and most importantly, I would like to thank my parents, Rick and Carol, for their love and support. More than any others, you made my dream possible. VITA July 7,1964 ......................................................... Born - Abington, Pennsylvania 1986 ......................... ........................................B.A. in Biology, Gettysburg College Gettysburg, PA 1986-1989 ............................................................Graduate Teaching Assistant, Philadelphia College of Pharmacy & Science, Philadelphia, PA 1990 ......................................................................M.Sc. in Pharmacology, Philadelphia College of Pharmacy & Science, Philadelphia, PA 1990-1992 ................................. ...................... Graduate Teaching Associate, College of Pharmacy, The Ohio State University, Columbus, OH PUBLICATIONS Layer, R.T., and R.O. Warwick. Contrasting effects of enalaprilat and phosphoramidon on bombesin-induced hypothermia in the rat. (1988) Society for Neurocience Abstract 14: 60.1. Hill, R., R. Layer, L. Wallace, T. Farooqui, N. Uretsky, and D. Miller. Synthesis and preliminary biological evaluation of substituted o-tyrosines as potential quisqualate analogs. (1989) American Association of Pharmaceutical Scientists Meeting. Layer, R.T., N.J. Uretsky, and L.J. Wallace. Competition between motor activating psychostimulants and morphine injected into the nucleus accumbens. (1990) The FASEB Journal 4: 4130. iv Layer, R.T., N.J. Uretsky, and L.J. Wallace. Effects of intra-accumbens injection of the glutamate antagonist DNQX on place preference and locomotor activity induced by amphetamine. (1991) Society for Neurocience Abstract 17: 567.14. Layer, R.T., N.J. Uretsky, and L.J. Wallace. Effects of Morphine in the Nucleus Accumbens on Stimulant-Induced Locomotion. (1991) Pharmacology, Biochemistry, and Behavior 40: 21-26. Layer, R.T., N.J. Uretsky, and L.J. Wallace. Effect of Serotonergic Agonists in the Nucleus Accumbens on d-Amphetamine-lnduced Locomotion. (1991) Life Sciences 50: 813-820. FIELDS OF STUDY Major field: Pharmacy Studies in: Pharmacology v TABLE OF CONTENTS DEDICATION .............................................................................................................. ii ACKNOWLEDGEMENTS .......................................................................................... Hi VITA .................................................................................................................................. iv LIST OF TA BLES......................................................................................................... x LIST OF FIG U R E S................... xi CHAPTER I INTRODUCTION................................................................................... 1 THEORY AND TERMINOLOGY.................................................................... 2 METHODS OF ASSESSING DRUG REW A RD......................................... 6 OPERANT REINFORCEMENT TECHNIQUES ............................ 7 SELF-ADMINISTRATION....................................................... 7 FACILITATION OF ELECTRICAL BRAIN STIMULATION ......................................................................... 9 DRUG DISCRIMINATION ..................................................... 9 NON-OPERANT TECHNIQUES..................................................... 10 CONDITIONED PLACE PREFERENCE ......................... 11 CONDITIONED REINFORCEMENT................................. 16 THE LOCOMOTOR ASSAY AND ITS RELATIONSHIP TO REW A RD ................................................................................................. 16 NEURAL SUBSTRATE OF DRUG REWARD AND LOCOMOTOR PHARMACOLOGY....................................................................................... 18 MOTIVATION AND DRIVE ............................................................ 19 vi ANATOMY OF THE REWARD SUBSTRATE 20 THE NUCLEUS ACCUMBENS....................................................... 23 ROLE OF DOPAMINE IN NUCLEUS ACCUMBENS ............... 30 ANATOMY OF DOPAMINERGIC PR O JEC TIO N S 30 BIOCHEMICAL PHARMACOLOGY OF DOPAMINE . 31 ELECTROPHYSIOLOGY OF DOPAMINE IN NUCLEUS ACCUMBENS..................................................... 32 ROLE OF NUCLEUS ACCUMBENS DOPAMINE IN BEHAVIOR........................................................................ 33 INTERACTION WITH DRUGS OF ABUSE WITH THE REWARD SUBSTRATE.......................................................... 35 PSYCHOSTIMULANTS.................................................................... 35 OPIATES ............................................................................................ 38 ETHANOL .................................. 41 NICOTINE .......................................................................................... 41 A9-TETRAHYDROCANNABINOL .................................................. 42 OTHER NEUROTRANSMITTER SYSTEMS INVOLVED IN REWARD AND LOCOMOTION............................................................ 43 PHARMACOLOGY OF THE EXCITATORY AMINO ACID SYSTEM ............................................................................................ 43 ENDOGENOUS LIGANDS................................................... 43 RECEPTORS AND PHARMACOLOGY............................ 44 BEHAVIORAL FUNCTIONS OF THE SYSTEM 52 PHARMACOLOGY OF OPIOIDS .................................................. 53 ENDOGENOUS LIGANDS.................................................. 53 RECEPTORS AND PHARMACOLOGY............................ 54 BEHAVIORAL FUNCTIONS OF THE SYSTEM 54 PHARMACOLOGY OF THE SEROTONIN SYSTEM ............... 56 ENDOGENOUS LIGANDS.................................................. 56 RECEPTORS AND PHARMACOLOGY............................ 56 BEHAVIORAL FUNCTIONS OF THE SYSTEM 58 vii STATEMENT OF THE PROBLEM 60 CHAPTER II THE ROLE OF EXCITATORY AMINO ACIDS IN DRUG REWARD .................................................................................................. 63 THE NMDA RECEPTOR ANTAGONIST MK-801 ELICITS CONDITIONED PLACE PREFERENCE IN R A TS ................................. 64 INTRODUCTION........................ 64 M ETH O D S ......................................................................... 65 RESULTS...........................................................................................