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Grabus submitted to the Faculty of the College of Arts and Sciences of American University in Partial Fulfillment of the Requirements for the Degree of Master of Arts in Psychology Chair: Anthony L J i j i John R. Glowa Dean of the College ft f a k /tftf 1998 American University Washington, D.C. 20016 THE AMERICAN UNIVERSITY LIBRARY Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number: 1388921 UMI Microform 1388921 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 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. AN ASSESSMENT OF NALORPHINE’S RELATIVE OPIOID EFFICACY WITHIN A CHOLECYSTOKININ DRUG DISCRIMINATION PROCEDURE BY Sheri D. Grabus ABSTRACT The partial agonist nalorphine appears to lie between naloxone (with little intrinsic activity) and morphine (with full intrinsic activity) on a continuum of relative efficacy (Smurthwaite & Riley, 1995). However, it is unclear whether nalorphine is more like naloxone or morphine. Using a drug discrimination procedure (Melton & Riley, 1993) that differentiated opioid antagonists and agonists on the basis of their ability to potentiate or block, respectively, CCK stimulus control, the present experiment attempted to assess nalorphine's relative efficacy. Nalorphine acted as an antagonist (i.e., potentiated CCK's stimulus properties) for some animals and as an agonist (i.e., blocked CCK stimulus control) for others, indicating that nalorphine may lie near the endogenous opiates on the continuum of relative efficacy. That is, in some animals nalorphine has less efficacy (i.e., acts as an opioid antagonist) and in others equal or greater efficacy than the endogenous opiates (i.e., acts as an opioid agonist). ii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS All my gratitude to Tony Riley for his persistence, wisdom and support during this long process. In addition, thanks to the remainder of my committee members, Scott Parker and John Glowa, for their input and advise. iii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS ABSTRACT..............................................................................................................ii ACKNOWLEDGEMENTS...................................................................................... iii LIST OF ILLUSTRATIONS......................................................................................v Chapter I. INTRODUCTION.........................................................................................1 II. M ETHO D.....................................................................................................5 Subjects ...................................................................................................... 5 Apparatus................................................................................................... 5 Drugs.......................................................................................................... 6 Procedure ................................................................................................... 6 Data Analysis..............................................................................................9 III. RESULTS..................................................................................................11 Acquisition ................................................................................................ 11 Generalization ....................................................................................... 11 CCK/Nalorphine Interactions ...................................................................15 IV. DISCUSSION........................................................................................... 21 BIBLIOGRAPHY................................................................................................... 32 iv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF ILLUSTRATIONS 1. Amount of saccharin consumed for individual subjects in Group L and for five subjects in Group W following various doses of CCK during generalization testing ........................................................................................ 12 2. Amount of saccharin consumed for individual subjects in Group L and for five subjects in Group W following various doses of nalorphine during generalization testing ............................................................................ 14 3. Amount of saccharin consumed for individual subjects in Group L following various doses of nalorphine in combination with a dose of CCK that produced intermediate levels of saccharin consumption when administered alone ..................................................................................16 4. Amount of saccharin consumed for individual animals in Group L at their training dose of CCK and at an ineffective dose of nalorphine combined with the training dose of CCK ......................................................... 18 5. Amount of saccharin consumed for a single subject in Group L in which various doses of nalorphine were given in combination with the training dose of CCK ........................................................................................ 20 v Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER I INTRODUCTION Partial opioid agonists are compounds that possess opioid activity, yet are not as efficacious as full agonists in their behavioral and physiological effects (Martin, 1967; Colpaert, 1986). As such, these compounds produce weak agonist effects when administered alone but decrease the effects of full agonists when given in combination (by preventing full agonists from binding to the receptor) (Holtzman, 1985). One such partial agonist is nalorphine. For example, nalorphine produces analgesia and respiratory depression (i.e., has opioid agonist activity), but when given in combination with morphine it blocks morphine's analgesic and respiratory depressive effects (i.e., demonstrates opioid antagonist activity) (Martin, 1967). In addition to demonstrations within these preparations, researchers have also examined nalorphine's partial agonist activity within drug discrimination learning, a design in which drugs serve as discriminative stimuli to control behavior (for reviews, see Overton, 1971; Colpaert, Niemegeers & Janssen, 1975; Schuster & Balster, 1977; Jarbe & Swedberg, 1982; Holtzman, 1985; Overton, Leonard & Merkle, 1986; Jarbe, 1987; Preston & Bigelow, 1991; Goudie & Leathley, 1993; Stolerman, 1993; fora bibliography on drug discrimination learning, see Stolerman, Samele, Kamien, Mariathasan & Hague, 1995). In this preparation, once an animal acquires the 1 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2 discrimination (e.g., pressing one lever for reinforcement in the presence of the drug stimulus and another lever for reinforcement in the absence of the training drug), other drugs may be administered alone or concurrently with the training drug to determine whether these compounds share, potentiate or block the stimulus properties of the training drug (Overton, 1971; Colpaert et al., 1975; Schuster & Balster, 1977; Holtzman, 1985; Overton etal., 1986; Jarbe, 1987; Goudie & Leathley,