University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2006-07-08 Development of Pharmacological Magnetic Resonance Imaging Methods and their Application to the Investigation of Antipsychotic Drugs: a Dissertation Karl F. Schmidt University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Animal Experimentation and Research Commons, Chemical Actions and Uses Commons, and the Diagnosis Commons Repository Citation Schmidt KF. (2006). Development of Pharmacological Magnetic Resonance Imaging Methods and their Application to the Investigation of Antipsychotic Drugs: a Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/w7am-qc46. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/ 114 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. A Dissertation Presented By Karl F. Schmidt Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY July 8, 2006 Program in Neuroscience COPYRIGHT Portions of this dissertation appear in the following publications and copyrighted manuscripts: Schmidt KF, Febo M, Shen Q, Luo F, Sicard KM, Ferris CF, Stein EA, Duong TQ. Hemodynamic and metabolic changes induced by cocaine in anesthetized rat observed with multimodal functional MRI. Psychopharmacology (Berl) 185: 479-86 (2006) Liu ZM, Schmidt KF, Sicard KM, Duong TQ. Imaging oxygen consumption in forepaw somatosensory simulation in rats under isoflurane anesthesia. Magn Reson Med 52: 277-285 (2004) Schmidt KF, Lemdiasov RA, Brevard M; Chen W, Fox GB, King JA, Ludwig R, Ferris CF. Simultaneous measurement of spin-echo BOLD and cerebral blood flow in the conscious rat using a three coil imaging and restraint system. Copyright © 2006 Journal of Neuroscience Methods, under review Ferris CF, Febo M, Luo F, Schmidt K, Brevard M, Harder JA, Kulkarni P, Messenger T, King JA. Functional magnetic resonance imaging in conscious animals: a new tool in behavioural neuroscience research. J Neuroendocrinol. 2006 May;18(5):307-18. ii Development of Pharmacological Magnetic Resonance Imaging Methods and Their Application to the Investigation of Antipsychotic Drugs A Dissertation Presented By Karl F. Schmidt Approved as to style and content by: David Weaver, Ph.D., Chair of Committee Jean King, Ph.D., Member of Committee Glenn Gaudette, Ph.D., Member of Committee Daniel Kilpatrick, Ph.D., Member of Committee Lino Becerra, Ph.D., External Member of Committee Craig Ferris, Ph.D., Thesis Advisor Anthony Carruthers, Ph.D., Dean of the Graduate School of Biomedical Sciences Ph.D. Program in Neuroscience June 16, 2006 iii ACKNOWLEDGMENTS I have been unusually fortunate as a graduate student to have had the opportunity to train under the direction of two mentors with very different interests and expertise. Dr. Timothy Duong was responsible for my training in my first years at UMASS Medical School and, following his progression to Emory University, I have had the great fortune to complete my training under the direction of Dr. Craig Ferris. I owe a tremendous debt of gratitude to both mentors, for their invaluable instruction in the technical aspects of MRI and in the application of MRI to pertinent problems in neuroscience. For years now, Dr. David Weaver has provided me with tireless and unwavering support in my scholastic and research efforts, without which I am confident that my progress would have stalled or failed, long ago. Similarly, the additional members of my research committee, Drs. Jean King, Glenn Gaudette, and Josie Harder, have provided me with the critical direction and support that I have needed in my research efforts, and I am truly grateful. I would like to thank the members of the examination committee, some of whom have already suffered through too many of my presentations, for contributing their valuable time in this final exercise, especially Drs. Lino Becerra and Daniel Kilpatrick. My colleagues at the CCNI have provided me with a broader education than I could possibly have anticipated. To be surrounded by such diverse medical and technical expertise has been a rare opportunity, and I thank Dr. Marcelo Febo, Mat Brevard, Tara Messenger, Dr. Li Zhixin, Dr. Ken Sicard, Dr. Praveen Kulkarni, Dr. Steve Bird, Dr. Nils iv Henninger, Dr. Wei Chen, and Dr. Feng Luo (now at Abbott Laboratories), as well as Govind Nair (now at Emory University) for their help and instruction over the past years. I owe this opportunity to pursue my doctorate to my mentors at Harvard Medical School, Drs. Mitch Albert, Yanping Sun, and Mary Mazzanti, for their training in prior years. I sincerely appreciate the support and direction given by Dr. Tony Carruthers in my first months at UMASS, and on a continuing basis thereafter, as well as the loving support and encouragement of my family. Several studies were made possible with the gracious financial support of Abbott Laboratories, and the valuable direction of Drs. Gerard Fox, Yanping Luo, Pamela Skoubis, Vincent Hradil, and Chih-Liang Chin. Overall, funding for this research was provided by Abbott Laboratories, the American Heart Association (SDG-0430020N), the National Institute on Drug Abuse (R01- DA13517), the National Institutes of Health (R01-EY014211), the University of Massachusetts Medical School, and the Whitaker Foundation (RG-02-0005). Finally, the word support does not begin to describe the emotional investment and daily contributions of another that have ultimately made this pursuit possible. What small portion of this effort that is mine to give, is dedicated to my loving wife, Rebecca. v ABSTRACT Pharmacological magnetic resonance imaging (phMRI) is the use of functional MRI techniques to elucidate the effects that psychotropic drugs have on neural activity within the brain; it is an emerging field of research that holds great potential for the investigation of drugs that act on the central nervous system by revealing the changes in neural activity that mediate observable changes in behavior, cognition, and perception. However, the realization of this potential is hampered by several unanswered questions: Are the MRI measurements reliable surrogates of changing neural activity in the presence of pharmacological agents? Is it relevant to investigate psychiatric phenomena such as reward or anxiolysis in anesthetized, rather than conscious animals? What are the methods that yield reproducible and meaningful results from phMRI experiments, and are they consistent in the investigations of different drugs? The research presented herein addresses many of these questions with the specific aims of 1) Developing pharmacological MRI methodologies that can be used in the conscious animal, 2) Validating these methodologies with the investigation of a non-stimulant, psychoactive compound, and vi 3) Applying these methodologies to the investigation of typical and atypical antipsychotic drugs, classes of compounds with unknown mechanisms of therapeutic action Building on recent developments in the field of functional MRI research, we developed new techniques that enable the investigator to measure localized changes in metabolism commensurate with changing neural activity. We tested the hypothesis that metabolic changes are a more reliable surrogate of changes in neural activity in response to a cocaine challenge, than changes observed in the blood-oxygen-level-dependent (BOLD) signal alone. We developed a system capable of multi-modal imaging in the conscious rat, and we tested the hypothesis that the conscious brain exhibits a markedly different response to systemic morphine challenge than the anesthetized brain. We identified and elucidated several fundamental limitations of the imaging and analysis protocols used in phMRI investigations, and developed new tools that enable the investigator to avoid common pitfalls. Finally, we applied these phMRI techniques to the investigation of neuroleptic compounds by asking the question: does treatment with typical or atypical antipsychotic drugs modulate the systems in the brain which are direct or indirect (i.e. downstream) substrates for a dopaminergic agonist? The execution of this research has generated several new tools for the neuroscience and drug discovery communities that can be used in neuropsychiatric investigations into the action of psychotropic drugs, while the results of this research provide evidence that supports several answers to the questions that currently limit the utility of phMRI investigations. Specifically, we observed that metabolic change can be measured to vii resolve discrepancies between anomalous BOLD signal changes and underlying changes in neural activity in the case of systemically administered cocaine. We found clear differences in the response to systemically administered morphine between conscious and anesthetized rats, and observed that only conscious animals exhibit a phMRI response that can be explained by the pharmacodynamics of morphine and corroborated by behavioral observations. We identified fundamental and drug-dependent limitations in the protocols used to perform phMRI investigations, and designed