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THE ABILITY OF PROGLUMIDE TO MODULATE CHANGES IN MORPHINE’S AVERS IVE PROPERTIES DURING CHRONIC MORPHINE EXPOSURE by Meredith A. Fox submitted to the Faculty of the College of Arts and Sciences of American University in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Psychology Chair: -- f t Anthony L. Riley Laura Dean df College of Arts and Sciences Scott Parker C.j s 'ha, Date ^ Cora Lee Wetherington^ 2003 American University Washington, DC 20016 AMERICAN UNIVERSITY LIBRARY Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number: 3100527 UMI UMI Microform 3100527 Copyright 2003 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. THE ABILITY OF PROGLUMIDE TO MODULATE CHANGES IN MORPINE’S AVERSIVE PROPERTIES DURING CHRONIC MORPHINE EXPOSURE by Meredith A. Fox ABSTRACT Just as chronic exposure to morphine alters its antinociceptive properties, chronic exposure to morphine has been shown to alter the strength of its aversive effects. As cholecystokinin (CCK) antagonists have been shown to prevent or reverse tolerance to morphine’s analgesic effects, such compounds could potentially modulate morphine’s aversive properties. The current experiment assessed the ability of the CCK antagonist proglumide to block the development of tolerance to the aversive properties of morphine in rats utilizing a conditioned taste aversion (CTA) design. Specifically, animals were preexposed to vehicle, morphine (5 mg/kg), proglumide (5 mg/kg) or a combination of proglumide administered either immediately or 15 min before morphine. On subsequent conditioning days, saccharin was presented followed immediately by administration of either morphine (10 mg/kg) or vehicle. Over conditioning, control animals increased saccharin consumption, regardless of preexposure condition. Animals preexposed to vehicle or proglumide and injected with morphine during conditioning acquired a morphine-induced saccharin aversion. Animals preexposed to morphine and conditioned with morphine acquired an attenuated morphine-induced saccharin aversion. Animals ii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. preexposed to the combination of proglumide and morphine and injected with morphine during conditioning also acquired an attenuated morphine-induced saccharin aversion. Importantly, saccharin consumption in animals preexposed to either proglumide- morphine combination was not different from animals preexposed to morphine, indicating that proglumide had no effect on the development of tolerance to the aversive properties of morphine in a CTA design. In order to assess whether the inability of proglumide to block the development of tolerance was due to the specific parameters of Experiment 1, Experiment 2 examined the effects of 5 mg/kg proglumide administered either immediately, 5 or 15 min before CCK (3 or 10 ptg/kg) on CCK-induced suppression of feeding. When proglumide was administered immediately before 3 pg/kg CCK, it attenuated the CCK-induced suppression of feeding. The findings from the current study suggest that CCK may not be involved in the aversive properties of morphine. iii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS ABSTRACT..............................................................................................................................ii LIST OF ILLUSTRATIONS................................................................................................. vi Chapter 1. INTRODUCTION..................................................................................................1 2. PROCEDURE: EXPERIM ENT!.................................................................... 12 Subjects Drugs and Solutions Phase 1: Habituation Phase 2: Preexposure Phase 3: Conditioning Test for Saccharin Aversion Statistical Analysis 3. RESULTS: EXPERIMENT 1............................................................................16 Preexposure Conditioning 4. DISCUSSION: EXPERIMENT 1................................ 22 5. PROCEDURE: EXPERIMENT 2 ................................................................... 27 Subjects iv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Drugs Phase 1: Habituation Phase 2: Drug Effects on Feeding Statistical Analysis 6. RESULTS: EXPERIMENT 2 ........................................................................... 29 7. DISCUSSION.......................................................................................................33 BIBLIOGRAPHY...................................................................................................................46 v Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF ILLUSTRATIONS 1. Mean (± S.E.M.) consumption of water over repeated preexposure days for subjects in Preexposure Groups PM, PiM, PV, VM and VV. Water was available 5 h before injections........................................................................16 2. Mean (± S.E.M.) consumption of saccharin over repeated conditioning trials for control subjects and subjects in Groups VM-M and VV-M. * Significantly different from baseline.................................................................. 18 3. Mean (± S.E.M.) consumption of saccharin over repeated conditioning trials for control subjects and subjects in Groups PM-M and PV-M. * Significantly different from baseline..................................................................19 4. Mean (± S.E.M.) consumption of saccharin over repeated conditioning trials for control subjects and subjects in Groups PiM-M and PV-M. * Significantly different from baseline..................................................................20 5. Mean (± S.E.M.) consumption of food for food-deprived subjects over repeated 60-min experimental sessions following saline, 10 pg/kg CCK, 3 pg/kg CCK or 5 mg/kg proglumide. * Significantly different from baseline (saline)...................................................................................................... 29 6. Mean (± S.E.M.) consumption of food for food-deprived subjects over repeated 60-min experimental sessions following saline, 10 pg/kg CCK or 5 mg/kg proglumide (P) followed either 15 or 5 min later by 10 pg/kg CCK. * Significantly different from baseline (saline)....................................... 30 7. Mean (± S.E.M.) consumption of food for food-deprived subjects over repeated 60-min experimental sessions following saline, 3 pg/kg CCK or 5 mg/kg proglumide (P) followed either 15 min later or immediately by 3 pg/kg CCK. * Significantly different from baseline (saline). **Significantly different from 3 pg/kg CCK alone. ***Significantly different from proglumide followed 15 min later by 3 pg/kg CCK..................32 vi Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER 1 INTRODUCTION Cholecystokinin (CCK) is a gastrointestinal hormone and one of the most widely distributed neuropeptides in the brain (Fink, Rex, Voits & Voigt, 1998), where it acts as a neurotransmitter (Mutt, 1994). CCK has been shown to be involved in many biological processes, including the reduction of food intake, the induction of anxiety-related behavior, and may be involved in learning and memory processes (for a review, see Crawley & Corwin, 1994; de Tullio, Delarge & Pirotte, 2000; Fink et al., 1998; Lindefors, Linden, Brene, Sedvall & Persson, 1993). CCK has also been shown to be involved in pain and antinociception/analgesia (for a review, see Wiesenfeld-Hallin & Xu, 1996), where it acts as an anti-opioid peptide (Wiesenfeld-Hallin, de Arauja, Alster, Xu & Hokfelt, 1999). In relation to its involvement in antinociception, the exogenous administration of CCK produces a physiological antagonism of morphine-induced antinociception (Faris, Komisaruk, Watkins & Mayer, 1983). For example, Faris et al. (1983) reported that rats injected with CCK 20 min prior to morphine displayed significantly attenuated morphine- induced analgesia, as assessed on the tail-flick test. CCK has also been found to reduce analgesia induced by endogenous opiates. Specifically, CCK administered 30 min before the delivery of foot shock to the front paws, which results in opiate-induced analgesia, reduced foot-shock induced analgesia (Faris et al., 1983). Nonopiate hind paw foot- 1 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2 shock analgesia was not reduced by CCK, suggesting that CCK specifically inhibits opiate analgesia (Faris et al., 1983). Thus, on an acute basis, CCK attenuates analgesia induced by both morphine and endogenous opiates, suggesting that CCK, as an endogenous opiate antagonist (Faris et al., 1983), may be released in response to opiate administration, returning the organism to its basal level of pain sensitivity (Watkins, Kinscheck & Mayer, 1985). Chronic morphine administration results in the development of tolerance to its antinociceptive effects (Zhou, Sun, Zhang & Han,