Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2014 CHARACTERIZATION OF THE DISCRIMINATIVE STIMULUS PROPERTIES OF THE ATYPICAL ANTIPSYCHOTIC AMISULPRIDE IN C57BL/6 MICE Timothy J. Donahue [email protected] Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Animal Studies Commons, and the Arts and Humanities Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/3607 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. CHARACTERIZATION OF THE DISCRIMINATIVE STIMULUS PROPERTIES OF THE ATYPICAL ANTIPSYCHOTIC AMISULPRIDE IN C57BL/6 MICE A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University By: TIMOTHY JOHN DONAHUE Bachelor of Arts, St. Mary’s Seminary University, Baltimore, Maryland 1973 Master of Education, Virginia Commonwealth University, 1976 Master of Humanities, University of Richmond, 1984 Master of Science, Virginia Commonwealth University, 2012 Director: Joseph H. Porter, Ph.D. Professor of Psychology Department of Psychology Virginia Commonwealth University Richmond, Virginia November, 2014 ii Acknowledgements I wish to express my gratitude to all of those who helped me conduct this research and aided in the crafting of this dissertation. First and foremost, I must thank my parents, Joseph and Lucille Donahue who fostered in me a love of reading and the value education. I know they would be proud of all this research represents. I remain continually appreciative for my undergraduate experience at St. Mary’s Seminary & University where my professors and fellow students created an environment that cherished the life of the mind and an appreciation for the complexity of life and human experience. It was at St. Mary’s that I first pondered the mystery of the natural world and developed my eclectic desire to understand that which we can see and that which we cannot. I wish to thank all my students and colleagues who travelled with me along my path as a career educator. They were and remain my companions in learning, my audience and needed critics. I am deeply appreciative of my mentor, and committee chair, Dr. Joseph H. Porter, for his support and guidance in my adventure as a graduate student in his Biopsychology Program. I have thoroughly enjoyed his friendship and oversight through the world of laboratory experimental research and our shared interest in the history of all things related to neuroscience. I am thankful of the assistance received from the Department of Psychology at Virginia Commonwealth University. Their support for me as an adult learner is proof positive of a university that that truly embraces diversity among its students; for me, that support was the chance of a lifetime. I am indebted to the many undergraduate students who worked on this research in our lab. Their energy and daily management of this project were critical to its development and completion. A very special thank you to fellow graduate students and lab partners, Todd Hillhouse and Kevin Webster, whose patience, watchful eye, expertise and laughter has aided in more ways than they will ever know. I wish to thank my dissertation committee members, Dr. Robert Hamm, Dr. Richard Young, Dr. Eliseu de Oliveira and Dr. Caroline Cobb for their guidance and insight into the scientific process and laboratory research. Most important of all, I must thank my wife, Marilee and my children Kevin, Caitlin and Eric whose presence in my life has made this experience all the more worthwhile. iii Table of Contents Page Acknowledgements………………………………………………………………………… ii List of Tables………………………………………………………………………………. v List of Figures……………………………………………………………………………… vi Abstract……………………………………………………………………………………. viii Introduction………………………………………………………………………………… 1 Synopsis of antipsychotic drugs in the treatment of schizophrenia……………………. 1 Schizophrenia………………………………………………………………………….. 2 Symptoms…………………………………………………………………………. 3 Disorganized thinking…………………………………………………………….. 5 Cognitive impairments……………………………………………………………. 6 Disorganized behavior…………………………………………………………….. 7 Negative symptoms………………………………………………………………... 7 Pharmacological Treatments for Schizophrenia………………………………………... 8 First generation typical antipsychotic medications……………………………….. 9 Second generation atypical antipsychotic medications…………………………….12 Amisulpride...……………………………………………………………………………14 History……………………………………………………………………………....14 Benzamides………………………………………………………………………….16 Receptor binding profile…………………………………………………………….17 Theories of Atypicality…………………………………………………………….. 20 Pharmacokinetic properties………………………………………………………... 23 Pharmacodynamic properties………………………………………………………. 27 Selectivity………………………………………………………………………….. 28 Role of dopamine autoreceptors…………………………………………………… 33 Adverse effects .………………………………………………………………….... 33 Dosage for treatment of depression………………………………………………... 36 Dosage for treatment of schizophrenia…………………………………………….. 39 Drug discrimination as a behavioral assay……………………………………………… 41 Brief history of drug discrimination with antipsychotic drugs……………………. 42 Drug discrimination with atypical antipsychotics…………………………………. 45 Beyond clozapine………………………………………………………………….. 47 Preliminary data……………………………………………………………………. 48 Amisulpride used in drug discrimination studies…………………………………...48 Rationale…………………………………………………………………………………… 51 Methods……………………………………………………………………………………. 56 Subjects…………………………………………………………………………….. 56 Drugs………………………………………………………………………………. 56 Apparatus…………………………………………………………………………... 57 Training procedures………………………………………………………………... 58 iv Phase I: Lever-lever training………………………………………………………. 58 Phase II: drug discrimination acquisition training………………………………… 59 Drug discrimination training criteria………………………………………………. 60 Phase III: generalization and substitution testing…………………………………. 60 Operational definitions of dependent variables…………………………………… 65 Data analysis………………………………………………………………………. 65 Results……………………………………………………………………………………… 67 rac-Amisulpride acquisition discrimination and generalization dose effect curves.. 67 rac-Amisulpride time course………………………………………………………. 70 Isomer substitution and rac-amisulpride generalization curves for combined cohort groups…………………………………………………………………...... 70 Benzamide derivatives substitution testing for sulpiride and (S)-sulpiride………. 72 Benzamide derivatives substitution testing for tiapride, nemonapride and Zacopride………………………………………………………………………….. 75 Substitution testing of typical antipsychotic medications: haloperidol, chlorpromazine, and non-selective dopamine agonist apomorphine…………... 75 Substitution testing of atypical antipsychotics: olanzapine, clozapine, risperidone, quetiapine, and aripiprazole……………………………………...... 79 Substitution testing of antidepressants fluoxetine and imipramine……………….. 80 Substitution testing of bupropion, mianserin, and chlordiazepoxide……………… 83 Substitution testing of selected dopaminergic ligands raclopride and quinpirole…. 83 Substitution testing of selected serotonin ligands BW-723C86 and SB-204741…. 86 Substitution testing of selective serotonin ligands LP-44 and SB-269970………. 86 Discussion…………………………………………………………………………………. 90 rac-Amisulpride as a discriminative stimulus…………………………………….. 90 Comparison of dose-effect curves…………………………………………………. 91 rac-Amisulpride time course………………………………………………………. 94 Benzamide substitution……………………………………………………………. 95 Typical antipsychotic drug substitution…………………………………………… 97 Atypical antipsychotic drug substitution………………………………………….. 99 Antidepressant substitution………………………………………………………… 102 Dopaminergic D2/3 selective ligand substitution testing………………………….... 104 Serotonin 5-HT2B selective ligand substitution testing……………………………. 104 Serotonin 5-HT7 selective ligand substitution testing…………………………….. 105 Autoreceptors………………………………………………………………………. 106 Future studies………………………………………………………………………. 107 Conclusion…………………………………………………………………………. 108 List of References………………………………………………………………………….. 110 Vita…………………………………………………………………………………………. 131 v List of Tables Page Table 1. Diagnostic criteria for schizophrenia…………………………………………. 4 Table 2. Dissociation rate constants for rac-amisulpride…………………………….. 19 Table 3. Pharmacokinetic properties of rac-amisulpride………………………………. 25 Table 4. Pharmacodynamic properties of rac-amisulpride…………………………….. 29 Table 5. Efficacy of amisulpride in patients with dysthymia: summary of data from randomized double-blind comparative studies………………..... 38 Table 6. Comparison of Ki binding profiles of amisulpride and its isomers 3 compared to antipsychotics on [ H]YM-09151 (D2), 3 3 [ H]ketanserin (5-HT2A) and [ H]clonidine (α2) binding ……………………... 49 Table 7. Receptor binding affinity Ki values (nM) for tested antipsychotic drugs at relevant receptor targets……………………………………………… 54 Table 8. Drugs tested for substitution to rac-amisulpride: doses and injection times………………………………………………………………… 61 Table 9. Receptor binding affinity Ki values (nM) for antidepressant drugs at relevant receptor targets to rac-amisulpride………………………………... 62 Table 10. Selective ligands for substitution test: Receptor Binding affinity Ki values (nM) and activity at relevant receptor targets………………………. 63 Table 11. Comparison of ED50 values for the three forms of amisulpride…………….. 92 Table