Show simple item record

dc.contributor.advisorSchahram Akbarian, M.D., Ph.D.
dc.contributor.authorSchroeder, Frederick Albert
dc.date2022-08-11T08:08:42.000
dc.date.accessioned2022-08-23T16:04:27Z
dc.date.available2022-08-23T16:04:27Z
dc.date.issued2007-12-28
dc.date.submitted2008-07-30
dc.identifier.doi10.13028/7bk0-a687
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31691
dc.description.abstractDepression and stimulant drug addiction each result in massive losses of health, productivity and human lives every year. Despite decades of research, current treatment regimes for depression are ineffective in approximately half of all patients. Therapy available to stimulant drug addicts is largely ineffective and moreover, dedicated treatments for drug dependence (including abuse of cocaine) are non-existent. Thus, there is a pressing need to further understanding of the molecular mechanisms underlying these disorders in order to develop novel, targeted therapeutic strategies. Chromatin remodeling, including changes in histone acetylation, has been proposed to play a role in both the etiology and treatment of depression and stimulant abuse. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate numerous cellular processes, including transcription, cell cycle progression and differentiation. Moreover, histone acetylation has been shown to regulate hippocampal neurogenesis, a cellular response associated with the pathogenesis and treatment of depression and stimulant abuse (Hsieh et al., 2004, Yamaguchi et al., 2004, Fischer et al., 2007). Ultimately, such basic cellular processes impact higher order function, namely cognition and emotion. Indeed, recent studies suggest that HDAC activity in selected forebrain regions, including ventral striatum and hippocampus, modulate stimulant- and antidepressantinduced behavior (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). These reports highlight an association between chromatin remodeling and diverse behavioral changes, including changes induced by the pleiotropic HDAC inhibitor, sodium butyrate (SB), (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). However, behavioral, brain-metabolic and molecular effects of SB treatment in the context of rodent models of depression, dopaminergic sensitization and repeated cocaine administration remained unclear. The work described in this thesis illustrates the potential for chromatin modifying drugs in mechanisms underlying the experimental pharmacology of depression and stimulant addiction. Specifically, the data presented here support the view that treatment with the short chain fatty acid, sodium butyrate enhances: (1) antidepressant-like behavioral effects of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (2) locomotor sensitization induced by repeated administration of the dopamine D1/D5 receptor agonist SKF82958; and (3) brain metabolic activation upon repeated cocaine administration as evidenced by fMRI in awake rats. Furthermore, this report provides evidence that these treatment paradigms will result in chromatin modification changes associated with active transcription, in addition to increased mRNA levels of plasticity-associated genes, including brain-derived neurotrophic factor (BDNF) at key brain regions implicated in the pathogenesis of depression and stimulant addiction. To date, little is known regarding the underlying mechanisms of action mediating the enhancing effects of sodium butyrate on the various antidepressant- and stimulantrelated paradigms. Our findings underscore the potential of chromatin-modifying drugs to profoundly affect the behavioral response of an animal to antidepressant and stimulant drugs and warrants consideration in the context of developing novel therapeutic strategies.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectHistone Deacetylases
dc.subjectCentral Nervous System Stimulants
dc.subjectAntidepressive Agents
dc.subjectSubstance-Related Disorders
dc.subjectDepressive Disorder
dc.subjectChromatin Assembly and Disassembly
dc.subjectButyrates
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCells
dc.subjectEnzymes and Coenzymes
dc.subjectGenetic Phenomena
dc.subjectMental Disorders
dc.subjectNervous System
dc.subjectTherapeutics
dc.titleA Role for Histone Modification in the Mechanism of Action of Antidepressant and Stimulant Drugs: a Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1370&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/370
dc.legacy.embargo2009-05-27T00:00:00-07:00
dc.identifier.contextkey560674
refterms.dateFOA2022-08-25T04:08:25Z
html.description.abstract<p>Depression and stimulant drug addiction each result in massive losses of health, productivity and human lives every year. Despite decades of research, current treatment regimes for depression are ineffective in approximately half of all patients. Therapy available to stimulant drug addicts is largely ineffective and moreover, dedicated treatments for drug dependence (including abuse of cocaine) are non-existent. Thus, there is a pressing need to further understanding of the molecular mechanisms underlying these disorders in order to develop novel, targeted therapeutic strategies.</p> <p>Chromatin remodeling, including changes in histone acetylation, has been proposed to play a role in both the etiology and treatment of depression and stimulant abuse. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate numerous cellular processes, including transcription, cell cycle progression and differentiation. Moreover, histone acetylation has been shown to regulate hippocampal neurogenesis, a cellular response associated with the pathogenesis and treatment of depression and stimulant abuse (Hsieh et al., 2004, Yamaguchi et al., 2004, Fischer et al., 2007). Ultimately, such basic cellular processes impact higher order function, namely cognition and emotion.</p> <p>Indeed, recent studies suggest that HDAC activity in selected forebrain regions, including ventral striatum and hippocampus, modulate stimulant- and antidepressantinduced behavior (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). These reports highlight an association between chromatin remodeling and diverse behavioral changes, including changes induced by the pleiotropic HDAC inhibitor, sodium butyrate (SB), (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). However, behavioral, brain-metabolic and molecular effects of SB treatment in the context of rodent models of depression, dopaminergic sensitization and repeated cocaine administration remained unclear.</p> <p>The work described in this thesis illustrates the potential for chromatin modifying drugs in mechanisms underlying the experimental pharmacology of depression and stimulant addiction. Specifically, the data presented here support the view that treatment with the short chain fatty acid, sodium butyrate enhances:<br /> (1) antidepressant-like behavioral effects of the selective serotonin reuptake inhibitor (SSRI), fluoxetine<br /> (2) locomotor sensitization induced by repeated administration of the dopamine D1/D5 receptor agonist SKF82958; and<br />(3) brain metabolic activation upon repeated cocaine administration as evidenced by fMRI in awake rats.</p> <p>Furthermore, this report provides evidence that these treatment paradigms will result in chromatin modification changes associated with active transcription, in addition to increased mRNA levels of plasticity-associated genes, including brain-derived neurotrophic factor (BDNF) at key brain regions implicated in the pathogenesis of depression and stimulant addiction.</p> <p>To date, little is known regarding the underlying mechanisms of action mediating the enhancing effects of sodium butyrate on the various antidepressant- and stimulantrelated paradigms. Our findings underscore the potential of chromatin-modifying drugs to profoundly affect the behavioral response of an animal to antidepressant and stimulant drugs and warrants consideration in the context of developing novel therapeutic strategies.</p>
dc.identifier.submissionpathgsbs_diss/370
dc.contributor.departmentPsychiatry
dc.description.thesisprogramNeuroscience


Files in this item

Thumbnail
Name:
Schroeder_Frederick.pdf
Size:
6.785Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record