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Effect of Imipramine and Classical Benzodiazepines on Stress-Induced

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Effect of Imipramine and Classical Benzodiazepines on Stress-Induced Effect of Imipramine and Classical Benzodiazepines on Stress-induced Neuroimmune Dysregulation and Behavior DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Karol Gabriela Ramirez Chan, DDS, MS Graduate Program in Oral Biology The Ohio State University 2015 Dissertation Committee: Dr. John F. Sheridan, advisor Dr. Ning Quan Dr. Michael Bailey Dr. John Walters Copyright by Karol Gabriela Ramírez Chan 2015 Abstract Psychosocial stress promotes brain-to-immune and immune-to-brain communication that can impact neurobiology and behavior. For example, exposure to stress is capable of causing peripheral immune dysregulation and neuroinflammatory signaling by repeated activation of neuroendocrine and autonomic pathways; that may contribute to the development of diseases and mental health disturbances. In order to relieve anxiety and depression accompanying stress, physicians resort to anxiolytics and antidepressants. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Moreover, imipramine, a tricyclic antidepressant effective in the treatment of mood disorders, has been reported to influence immune function in depressed patients. The potent impact of social stress on human’s health led to the development of representative animal models that emulate the pathophysiology of mental health disorders. The stress model of repeated social defeat (RSD), recapitulates many of the stress-driven alterations in both the periphery and central nervous system seen in humans experiencing chronic or repeated forms of stress (Hanke et al., 2012). For example, RSD triggered egress of inflammatory myeloid progenitor cells that traffic to blood, spleen and brain. RSD promoted brain region-specific activation of microglia/macrophages that led ii to prolonged anxiety. In parallel, RSD promoted long-lasting social avoidant behavior. Thus, the overall aim of this dissertation was to determine if pharmacologic blockade of the GABAergic and monoaminergic circuits using lorazepam, clonazepam, and imipramine, respectively, would: 1) prevent stress-induced peripheral and central inflammatory responses, and 2) block anxiety and social avoidance behavior in mice subjected to RSD. Treatment with lorazepam or clonazepam prior to stressor exposure affected central and peripheral responses. Treatment with either drug was effective in attenuating mRNA expression of corticotropin-releasing hormone (CRH) in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced elevated levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited the release of monocytes and granulocytes to circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam blocked stress-induced accumulation of macrophages in the brain. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior in mice exposed to RSD. Imipramine inhibits the reuptake of serotonin, norepinephrine, and dopamine on presynaptic neurons, and thus increases synaptic levels of these neurotransmitters. Antidepressants can stimulate adaptive changes in the central monoaminergic circuitry, which can modulate immune reactivity and the central actions of cytokines (Miller et al., iii 2009). In the present study, imipramine attenuated stress-induced corticosterone and IL-6 in plasma. Imipramine also decreased the percentage of monocytes and granulocytes in the bone marrow and circulation. However, imipramine did not prevent splenomegaly, stress-related increased percentage of granulocytes in this organ, and the production of pro-inflammatory cytokines in the spleen, following RSD. Imipramine abated the accumulation of macrophages in the brain in mice exposed to RSD. Imipramine treatment prior to stress exposure blocked neuroinflammatory signaling and stress-related anxiety- and depressive-like behavior. Finally, administration of imipramine for 24 days after stress termination reversed social avoidance behavior. Moreover, 24 days of imipramine treatment decreased stress- induced mRNA levels for IL-6 in brain microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of IL-6, TNF-α, and IL-1β, and this was reversed by imipramine treatment. These data suggest that the antidepressant imipramine may exert its effect, in part, by down-regulating microglial activation. These data support the notion that pharmacomodulation of the GABAergic and monoaminergic systems, besides exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during stress. iv Dedication Dedicated to María Rosa and Claudia, my beautiful grandmothers. The lessons you both taught me have shaped who I am today. My brother, Gabriel. You’re the greatest gift of life! And my parents, heroes forever, Rodrigo and Dory. Thank you for everything you have done for me! v Acknowledgments First, I would like to extend my gratitude to Dr. John Sheridan for believing in my potential and opening the doors of his laboratory to obtain my Doctor in Philosophy Degree. You have inspired me to pursue my goals with hard work and perseverance. Thank you for your time and mentoring. I really look forward to the day I can do the same for someone else. Second, I would like to thank fellow graduate students Dan McKim and Anzela Niraula for their generous help and guidance. Special thanks to post-doctoral fellows Dr. Brenda Reader, Dr. Brant Jarrett, and Dr. Seung Yung (David) for sharing their scientific knowledge. Third, I would like to thank technicians Daniel Shea, David Hammond, Yufen Wang, Juan Carlo Avalon, undergraduate students, Tom Zhang, January Kim, Ana Sucaldito, Rahul Gupta, Jenna Patterson, and post-doctoral fellow Sabrina Lisboa for their assistance in the experiments outlined below. vi I would like to acknowledge the committee members for their time and dedication in all the stages in the pursuit of my degree. Thanks to Dr. Quan, Dr. Bailey, and Dr. Walters. I will be forever grateful with the College of Dentistry of The Ohio State University for supporting my doctoral training financially. To conclude, I would like to thank the University of Costa Rica for providing the means in getting further training in research. Special thanks, to faculty members that have facilitated my professional development. vii Vita October 29, 1977 ............................................Born, San José, Costa Rica 1996................................................................Lincoln High School, San José, Costa Rica 2002................................................................Doctor of Dental Surgery, Universidad Latina de Costa Rica, San José, Costa Rica 2006................................................................Certificate in Periodontology, Pontificia Universidad Javeriana, Bogotá, Colombia 2007-Present ..................................................Professor, Facultad de Odontología, Universidad de Costa Rica, San José, Costa Rica 2012................................................................Master of Science, Post-Doctoral Master in Clinical and Translational Research, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico 2012-Present ..................................................Graduate Research Associate, Department of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio, USA viii Publications Elias Boneta AR , Ramirez K, Naboa J, Mateo LR, Stewart B, Panagokos F, De Vizio W. J. Efficacy in reducing dentine hypersensitivity of a regimen using a toothpaste containing 8% arginine and calcium carbonate, a mouthwash containing 0.8% arginine, pyrophosphate and PVM/MA copolymer and a toothbrush compared to potassium and negative control regimens: an eight-week randomized clinical trial. Journal of Dentistry. 2013 Mar; 41 Suppl 1:S42-9. Ramirez K, García-Rodríguez O, Murillo-Arocho M, Fernández-López O, Elías-Boneta AR. Dentogingival complex: dimension based on biotypes. Puerto Rico Health Sciences Journal. 2013 Dec;32 (4):182-6 Ramirez K, Shea DT, McKim DB, Reader BF, Sheridan JF. Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behavior and Immunity. 2015 Feb 18. pii: S0889-1591(15)00024-0. doi:10.1016/j.bbi.2015.01.016. ix Ramirez K, Niraula A, Shea DT, Sheridan JF. GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations. Brain, Behavior, and Immunity (In Review). Ramirez K, Sheridan JF. Antidepressant imipramine rescues stress-induced inflammation in the periphery and central nervous system and related anxiety-and depressive like behaviors (In preparation). Fields of Study Major Field: Oral Biology Area of specialization: Immunology and Inflammation Research Area: Stress x Table of Contents Abstract ............................................................................................................................... ii Dedication ........................................................................................................................... v Acknowledgments.............................................................................................................
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