Opioid Drug Discrimination: Characterization of the Morphine Stimulus
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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. ProQuest Information and Learning 300 North Zeeb Road. Ann Arbor. Ml 48106-1346 USA 800-521-0600 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission ofof the the copyright copyright owner. owner. Further Further reproduction reproduction prohibited prohibited without without permission. permission. OPIOID DRUG DISCRIMINATION: CHARACTERIZATION OF THE MORPHINE STIMULUS. by Glenn William Stevenson 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: Anthonvltnonv L. Riley, Ph.D. UP Glowa, Ph.D. Dean “of the College o f Arts and Sciences 3 * Date 2002 American University Washington, D C. 20016 Miencm nmEHnx iMMk Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number 3048288 UMI* UMI Microform 3048288 Copyright 2002 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. © COPYRIGHT by GLENN STEVENSON 2002 ALL RIGHTS RESERVED Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. OPIOID DRUG DISCRIMINATION: CHARACTERIZATION OF THE MORPHINE STIMULUS BY Glenn William Stevenson ABSTRACT There have been few assessments of delta receptor activity in morphine drug discrimination learning (DDL) and these assessments have been limited to nonselective compounds or selective delta peptides administered i.c.v. Experiment 1 assessed the role of the delta receptor in the mediation of morphine drug discrimination by examining the ability of the systemicaily- administered, delta opioid agonist SNC80 to substitute for (and the delta opioid antagonist naltrindole to antagonize) morphine stimulus effects in rats trained to discriminate morphine from its vehicle in the conditioned taste aversion baseline of drug discrimination learning. Although morphine and methadone produced dose-related substitution for morphine (10 mg/kg), there was no evidence of substitution for morphine by SNC80 at any dose tested. Further, although naloxone (3.2 mg/kg) completely blocked the discriminative effects of morphine, naltrindole (3.2 -1 0 mg/kg) did not significantly affect the morphine stimulus. These data suggest that the discriminative control established to morphine is mediated by its activity at the mu, but not the delta, receptor. ii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The failure of SNC80 to substitute for morphine may be due to the general inability of activity at the delta receptor to support discrimination learning. To test this, Experiment 2 assessed the establishment of discriminative control by the selective delta agonist SNC80 in rats and its generalization to and antagonism by compounds relatively selective to the delta and mu receptor subtypes using the conditioned taste aversion baseline of DDL. Following acquisition, SNC80 and the delta agonist SNC162 produced SNC80-appropriate responding at a dose of 18 mg/kg. Conversely, the mu agonist morphine produced vehicle-appropriate responding at all doses tested. The discriminative effects of SNC80 were maximal at 20 min, partial at 120 min and lost at 240 min. These selective generalization patterns with SNC162 and morphine suggest that the discriminative effects of SNC80 were mediated at the delta, but not the mu, receptor, a conclusion supported by the fact that SNC80’s discriminative control was completely blocked by the delta-selective antagonist naltrindole (NTI), but not by the mu-selective antagonist naltrexone. The present findings indicate that the discriminative effects of morphine are mediated at the mu, but not the delta, receptor. iii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS ABSTRACT............................................................................................... ii TABLE OF CONTENTS.............................................................................. iv LIST OF ILLUSTRATIONS.......................................................................... vi Chapter 1. EXPERIMENT 1............................................................................1 2. METHOD..................................................................................... 9 Subjects and Apparatus Drugs Procedure Data Analyses 3. RESULTS................................................................................... 14 4. DISCUSSION.............................................................................. 27 5. EXPERIMENT 2........................................................................... 30 6. METHOD .................................................................................... 35 Subjects and Apparatus Drugs Procedure Data Analyses 7. RESULTS................................................................................... 40 iv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1. DISCUSSION.............................................................................. 56 2. GENERAL DISCUSSION..............................................................59 BIBLIOGRAPHY......................................................................................... 71 v Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF FIGURES 1. Mean amount (±S.E.M.) of saccharin consumption for subjects in Groups ML and MW during Water Baseline (W) and Saccharin Habituation (S) and throughout the first seven conditioning cycles. * Significantly different between Groups ML and MW. ** For Group ML, significantly different from Trials 1 and 2. 16 2. Mean amount of saccharin consumption (±S.E.M) for subjects in Groups ML and MW during recovery (R) and conditioning (C) and following various doses of morphine (1.8 -10 mg/kg). * Significantly different between Groups ML and MW. ** For Group ML, significantly greater than consumption at 10 mg/kg. *** For Group ML, significantly greater than consumption at 5.6 mg/kg 18 3. Mean amount of saccharin consumption (±S.E.M) for subjects in Groups ML and MW during recovery (R) and conditioning (C) and following various doses of methadone (3.2 - 7.5 mg/kg. * Significantly different between Groups ML and MW. ** For Group ML, significantly different from consumption at 6.5 and 7.5 mg/kg. *** For Group MW, significantly different from consumption at 7.5 mg/kg........................................................................................................ 20 4. Mean amount of saccharin consumption (±S.E.M) for subjects in Groups ML and MW during recovery (R) and conditioning (C) and following various doses of SNC80 (3.2 - 24 mg/kg). *** For Group ML, significantly different from consumption at 24 mg/kg ............................................................................ 22 5. Mean amount of saccharin consumption (±S.E.M) for subjects in Groups ML and MW following the naloxone/morphine combination. * Significantly different between Groups ML and MW. ** For Group ML, significantly different from consumption at 0 mg/kg. *** For Group MW, significantly different from consumption at 3.2 mg/kg ........................................................................... 24 6. Mean amount of saccharin consumption (±S.E.M) for subjects in Groups ML and MW following the naltrindole/morphine combination. * Significantly different between Groups ML and MW. ** For Group MW, significantly different from consumption at 0, 3.2 and 5.6 mg/kg ................................................... 26 7. Mean amount (± S.E.M) of saccharin consumption for subjects in Groups SL and SW during Water Baseline (W) and Saccharin Habituation (S) and throughout the first seven conditioning cycles. * Significantly different between Groups SL and SW. ** For Group SL, significantly