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University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 7-1-2020 An Investigation of Motivational Dysfunctions in a Rat Model of Effort-Related Choice Behavior: Behavioral and Neurochemical Evidence for Possible Novel Pharmacological Treatments Renee A. Rotolo University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Rotolo, Renee A., "An Investigation of Motivational Dysfunctions in a Rat Model of Effort-Related Choice Behavior: Behavioral and Neurochemical Evidence for Possible Novel Pharmacological Treatments" (2020). Doctoral Dissertations. 2575. https://opencommons.uconn.edu/dissertations/2575 An Investigation of Motivational Dysfunctions in a Rat Model of Effort-Related Choice Behavior: Behavioral and Neurochemical Evidence for Possible Novel Pharmacological Treatments Renee A. Rotolo, Ph.D. University of Connecticut, 2020 Motivational symptoms such as fatigue, anergia, and amotivation are seen in depression, Parkinson’s disease, schizophrenia, and other disorders. These symptoms are often left untreated by the most frequently prescribed antidepressants, which typically block serotonin transport. Considerable evidence implicates brain dopamine (DA) in the regulation of behavioral activation and effort-related aspects of motivation. Animal studies of effort-based choice are being used to provide formal models of motivational dysfunctions in humans. Drugs that block DA transport (DAT) are able to reverse the effort-related effects of the vesicular monoamine transport inhibitor tetrabenazine, a drug that blocks DA storage and depletes DA. Many of the existing DAT inhibitor drugs are either classic DA blockers such as cocaine, or drugs that also stimulate release of DA. These drugs can produce a number of undesirable side effects, including psychotic symptoms and abuse liability. Thus, there is a need to develop and characterize novel atypical DAT inhibitors that are relatively selective and have unique binding profiles. The completed studies discussed here focus on the behavioral and neurochemical characterization of several recently synthesized atypical DAT inhibitors, with the aim of identifying a novel family of drugs that may be useful for the treatment of motivational dysfunctions in humans, and the development of physiological markers of the selection of high-effort instrumental behavior. In recent years, human imaging and neurophysiological studies have had sought to identify the neural processes involved in motivation, psychomotor retardation, anergia, and lassitude in Renee Rotolo, University of Connecticut, 2020 depression and other disorders. Human studies have suggested that there is frontal electroencephalography (EEG) asymmetry in depressed patients, but physiological correlates of effort-related motivational dysfunction have not been identified in animals. To complement the investigation of effort-related impairments using pharmacological approaches, the final experiment involved the measurement of frontal cortex EEG activity of animals under pharmacological manipulation of DA transmission. Ultimately, the development of a physiological marker of effort-related dysfunction in a preclinical model may be critical for identifying the brain circuits involved in regulating these behaviors that can be readily translated to human studies. Together, results from these experiments may contribute to the identification of novel treatment options for motivational dysfunctions. An Investigation of Motivational Dysfunctions in a Rat Model of Effort-Related Choice Behavior: Behavioral and Neurochemical Evidence for Possible Novel Pharmacological Treatments Renee A. Rotolo B.S., Quinnipiac University, 2013 M.S., Quinnipiac University, 2015 A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Connecticut 2020 Copyright by Renee Aidan Rotolo 2020 i APPROVAL PAGE Doctor of Philosophy Dissertation An Investigation of Motivational Dysfunctions in a Rat Model of Effort-Related Choice Behavior: Behavioral and Neurochemical Evidence for Possible Novel Pharmacological Treatments Presented by Renee Aidan Rotolo, B.S., M.S. Major Advisor ___________________________________________________________ John D. Salamone Associate Advisor ________________________________________________________ Etan Markus Associate Advisor ________________________________________________________ James Chrobak University of Connecticut 2020 ii ACKNOWLEDGEMENTS I would like to thank my advisor Dr. John Salamone for his unwavering guidance, support, and reassurance, and for many fun conversations as a member of the team in his lab at UConn. I would also like to acknowledge Dr. Mercè Correa, Dr. Etan Markus, Dr. James Chrobak, and Dr. Gregory Sartor for their support and feedback as my committee members, mentors, and friends. I would like to thank my fellow graduate students, Rose Presby, Jen-Hau Yang, Naixin Ren, and Emma Zorda for their advice, assistance, and camaraderie. A very special thanks goes to Dr. Adrienne Betz, for sparking my love of neuroscience, for introducing me to John, and for remaining an advisor and close friend. Thank you to my friends, family, and husband for their encouraging words, and for keeping me on my toes by constantly asking what my research is about. Thank you to all of the Salamone Lab undergraduates, the animal care staff, and the rats, without whom this work would not be possible. Finally, I would like to thank our collaborators and funding sources: Acadia Pharmaceuticals BlackThorn Therapeutics Chronos Therapeutics Connecticut Institute for Brain and Cognitive Sciences Gert Lubec Laboratory Lundbeck Pharmaceuticals National Institute of Mental Health (NIMH) NIMH R01MH121359; NIMH R03MH112984 University of Connecticut Psychological Sciences Undergraduate Grants University of Connecticut Research Foundation Grants to JD Salamone University of Connecticut Summer Undergraduate Research Fund iii TABLE OF CONTENTS Chapter 1: Background Role of Dopamine (DA) in Motivated Behaviors…………………………………………1 Motivational Aspects of Depression……………………………………………………....2 Pharmacological Models of Fatigue and Anergia in Rats………………………………....3 Classical vs. Atypical Dopamine Transport Inhibitors…………………………………….4 Development of Physiological Measures of Effort-Related Aspects of Motivation……... 6 Present Work………………………………………………………………………………8 Chapter 2: Evaluation of the effort-related effects of chronic administration of the DA D2 receptor antagonist haloperidol via subcutaneous minipumps. Introduction………………………………………………………………………………10 Materials and Methods…………………………………………………………………...12 Results……………………………………………………………………………………15 Figures……………………………………………………………………………………18 Chapter 3: The novel atypical dopamine uptake inhibitor (S)-CE-123 partially reverses the effort-related effects of the dopamine depleting agent tetrabenazine and increases progressive ratio responding. Introduction………………………………………………………………………………21 Materials and Methods…………………………………………………………………...24 Results……………………………………………………………………………………30 Figures……………………………………………………………………………………33 Chapter 4: Behavioral and dopamine transporter binding properties of the modafinil analog (S, S)-CE-158: reversal of the motivational effects of tetrabenazine and enhancement of progressive ratio responding. Introduction………………………………………………………………………………38 Materials and Methods…………………………………………………………………...41 Results……………………………………………………………………………………48 Figures……………………………………………………………………………………51 Chapter 5: An assessment of the atypical DA transport inhibitor CT-005404 for its ability to reverse the effort-related effects of tetrabenazine, to reverse the effort-related effects of the pro-inflammatory cytokine IL-1β, and to increase progressive ratio responding. Introduction………………………………………………………………………………57 Materials and Methods…………………………………………………………………...60 Results……………………………………………………………………………………67 Figures……………………………………………………………………………………70 iv Chapter 6: Effort-related effects of altering lever pressing ratio requirements, and of tetrabenazine administration, on progressive ratio work output. Introduction………………………………………………………………………………77 Materials and Methods…………………………………………………………………...81 Results……………………………………………………………………………………84 Figures……………………………………………………………………………………86 Chapter 7: Exploration of frontal cortex electrophysiology in freely moving untrained rats: effects of TBZ. Introduction………………………………………………………………………………90 Materials and Methods…………………………………………………………………...94 Results……………………………………………………………………………………97 Figures……………………………………………………………………………………98 Chapter 8: Discussion Summary of Results…………………………………………………………………….101 Chapter 2 Discussion……………………………………………………………….…..103 Chapter 3 Discussion…………………………………………………………….……..108 Chapter 4 Discussion…………………………………………………………….……..114 Chapter 5 Discussion……………………………………………………………….…..118 Chapter 6 Discussion…………………………………………………………….……..122 Chapter 7 Discussion……………………………………………………………….…..125 General Discussion and Conclusions…………………………………………….……..128 Summary of Appendices……………………………………………………………………...133 Appendix 1: Investigation of SSRI-induced fatigue in effort-related choice tasks, and of several selective serotonin receptor antagonists as potential treatment strategies. Introduction……………………………………………………………………………..134 Materials and Methods………………………………………………………………….136 Results…………………………………………………………………………………..137 Discussion………………………………………………………………………………141