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KRC thesis (7-07-15).pdf (2.43 MB)

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Effect of Imipramine and Classical Benzodiazepines on Stress-induced Neuroimmune Dysregulation and Behavior

Ramirez Chan, Karol Gabriela
http://rave.ohiolink.edu/etdc/view?acc_num=osu1436543143

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Dentistry.
Psychosocial stress promotes brain-to-immune and immune-to-brain communication that can impact neurobiology and behavior. Exposure to stress may cause peripheral immune dysregulation and neuroinflammatory signaling by repeated activation of neuroendocrine and autonomic pathways; that may contribute to the development of mental health disturbances. In order to relieve anxiety and depression accompanying stress, physicians resort to anxiolytics and antidepressants. Lorazepam and clonazepam are anxiolytics that act by enhancing GABAergic activity in the brain. Moreover, imipramine, a tricyclic antidepressant, has been reported to influence immune function in depressed patients. 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. 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 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. 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-and depressive-like behavior in mice exposed to RSD. Antidepressants can stimulate adaptive changes in the central monoaminergic circuitry, which can modulate immune reactivity. 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. Imipramine abated the accumulation of macrophages in the brain in mice exposed to RSD. Imipramine blocked neuroinflammatory signaling and stress-related anxiety-and depressive-like behavior. Administration of imipramine for 24 days after stress termination reversed social avoidance behavior and decreased stress-induced mRNA levels for IL-6 in microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of pro-inflammatory cytokines, and this was reversed by imipramine. 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.
John Sheridan (Advisor)
Ning Quan (Committee Member)
John Walters (Committee Member)
Michael Bailey (Committee Member)
152 p.
Immunology; Neurosciences
psychosocial stress, social defeat, imipramine, benzodiazepines, anxiety, depression

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Citations

  • Ramirez Chan, K. G. (2015). Effect of Imipramine and Classical Benzodiazepines on Stress-induced Neuroimmune Dysregulation and Behavior [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1436543143

    APA Style (7th edition)

  • Ramirez Chan, Karol. Effect of Imipramine and Classical Benzodiazepines on Stress-induced Neuroimmune Dysregulation and Behavior. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1436543143.

    MLA Style (8th edition)

  • Ramirez Chan, Karol. "Effect of Imipramine and Classical Benzodiazepines on Stress-induced Neuroimmune Dysregulation and Behavior." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1436543143

    Chicago Manual of Style (17th edition)

osu1436543143
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This open access ETD is published by The Ohio State University and OhioLINK.