{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/3306"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/3306","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Role of BDNF-TrkB Signaling in Cocaine Addiction","abstract":"Cocaine addiction results in neuroadaptations and drug-induced neuroplasticity that promote changes in protein expression and neuron morphology. Cocaine-induced increases in dopamine ultimately alter dopamine signaling in brain regions modulating reward and motivation, specifically the nucleus accumbens (NAc), and downstream proteins. One protein of particular interest is brain-derived neurotrophic factor (BDNF), a modulator of cell survival, viability, and plasticity. Cocaine has been shown to increase BDNF mRNA and protein levels in the NAc shell. In addition, intra-NAc infusions of BDNF have been demonstrated to increase cocaine intake and motivation for cocaine. These increases in BDNF also lead to activation of its receptor, tropomyosin receptor kinase B (TrkB). Studies indicate that the loss of TrkB specifically in the NAc shell reduced the reinforcing effects of cocaine using a self-administration paradigm, and also psychomotor effects of cocaine on activity; however, the contributions of each signaling pathway are unknown. Chapter 3 examined the creation of a cell-type specific herpes simplex viral (HSV) vector system to over-express wildtype TrkB or its docking mutants. In vivo and cell culture experiments indicated very weak viral expression, while cocaine self-administration testing produced inconsistent and inconclusive results. Chapter 4 examined cocaine-induced BDNF-TrkB receptor signaling using an adeno-associated viral vector system to over-express wildtype TrkB and its signaling mutants, more generally across NAc cell types. Initial self-administration testing suggested that overexpression of kinase dead TrkB (TrkB K571N) in the NAc shell increased the threshold dose required to maintain self-administration on the dose-response test and reduced motivation for cocaine. Subsequent behavioral testing did not confirm these results. Preliminary tissue staining demonstrated similar levels of viral infectivity between AAV-GFP and AAV-TrkB WT; however, subsequent tissue staining demonstrated very weak to no viral expression, consistent with the lack of consistent behavioral results. Finally, Chapter 5 utilized a transient but efficacious HSV vector system to over-express wildtype TrkB and its signaling mutants during cocaine-induced activation of the BDNF-TrkB receptor signaling pathway. Self-administration testing suggested that the kinase dead TrkB viral mutant (HSV-TrkB K571N) inversely affected cocaine taking and motivation for cocaine. In contrast to the cell-specific HSV vectors tested earlier, immunohistochemical techniques indicated stronger and consistent expression of these HSV-TrkB viruses; however, TrkB signaling-specific protein expression was not found. These findings indicate an inconsistency between behavioral results and viral expression, yet suggest that further experimentation is warranted.","abstract_html":"Cocaine addiction results in neuroadaptations and drug-induced neuroplasticity that promote changes in protein expression and neuron morphology. Cocaine-induced increases in dopamine ultimately alter dopamine signaling in brain regions modulating reward and motivation, specifically the nucleus accumbens (NAc), and downstream proteins. One protein of particular interest is brain-derived neurotrophic factor (BDNF), a modulator of cell survival, viability, and plasticity. Cocaine has been shown to increase BDNF mRNA and protein levels in the NAc shell. In addition, intra-NAc infusions of BDNF have been demonstrated to increase cocaine intake and motivation for cocaine. These increases in BDNF also lead to activation of its receptor, tropomyosin receptor kinase B (TrkB). Studies indicate that the loss of TrkB specifically in the NAc shell reduced the reinforcing effects of cocaine using a self-administration paradigm, and also psychomotor effects of cocaine on activity; however, the contributions of each signaling pathway are unknown. Chapter 3 examined the creation of a cell-type specific herpes simplex viral (HSV) vector system to over-express wildtype TrkB or its docking mutants. In vivo and cell culture experiments indicated very weak viral expression, while cocaine self-administration testing produced inconsistent and inconclusive results. Chapter 4 examined cocaine-induced BDNF-TrkB receptor signaling using an adeno-associated viral vector system to over-express wildtype TrkB and its signaling mutants, more generally across NAc cell types. Initial self-administration testing suggested that overexpression of kinase dead TrkB (TrkB K571N) in the NAc shell increased the threshold dose required to maintain self-administration on the dose-response test and reduced motivation for cocaine. Subsequent behavioral testing did not confirm these results. Preliminary tissue staining demonstrated similar levels of viral infectivity between AAV-GFP and AAV-TrkB WT; however, subsequent tissue staining demonstrated very weak to no viral expression, consistent with the lack of consistent behavioral results. Finally, Chapter 5 utilized a transient but efficacious HSV vector system to over-express wildtype TrkB and its signaling mutants during cocaine-induced activation of the BDNF-TrkB receptor signaling pathway. Self-administration testing suggested that the kinase dead TrkB viral mutant (HSV-TrkB K571N) inversely affected cocaine taking and motivation for cocaine. In contrast to the cell-specific HSV vectors tested earlier, immunohistochemical techniques indicated stronger and consistent expression of these HSV-TrkB viruses; however, TrkB signaling-specific protein expression was not found. These findings indicate an inconsistency between behavioral results and viral expression, yet suggest that further experimentation is warranted.","abstract_has_math":false,"creators":["Buzin, Nicole Renee"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Goldberg, Matthew S.","Monteggia, Lisa","Rothenfluh, Adrian","Self, David W."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016-06-27T20:02:39Z","date_published":"2016-06-27T20:02:39Z","updated_at":"2026-07-24T05:52:13Z","subjects":["Brain-Derived Neurotrophic Factor","Cocaine-Related Disorders","Nucleus Accumbens","Receptor, trkB"],"languages":["en_US"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["952355655"],"render_values":[{"text":"952355655","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/3306","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Goldberg, Matthew S.","Monteggia, Lisa","Rothenfluh, Adrian","Self, David W."]},{"key":"dc:creator","label":"Author","values":["Buzin, Nicole Renee"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2016-06-27T20:02:39Z","2014-05","2014-04-14","May 2014","2016-06-27T19:48:27Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Brain-Derived Neurotrophic Factor","Cocaine-Related Disorders","Nucleus Accumbens","Receptor, trkB"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en_US"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/3306","952355655"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Cocaine addiction results in neuroadaptations and drug-induced neuroplasticity that promote changes in protein expression and neuron morphology. Cocaine-induced increases in dopamine ultimately alter dopamine signaling in brain regions modulating reward and motivation, specifically the nucleus accumbens (NAc), and downstream proteins. One protein of particular interest is brain-derived neurotrophic factor (BDNF), a modulator of cell survival, viability, and plasticity. Cocaine has been shown to increase BDNF mRNA and protein levels in the NAc shell. In addition, intra-NAc infusions of BDNF have been demonstrated to increase cocaine intake and motivation for cocaine. These increases in BDNF also lead to activation of its receptor, tropomyosin receptor kinase B (TrkB). Studies indicate that the loss of TrkB specifically in the NAc shell reduced the reinforcing effects of cocaine using a self-administration paradigm, and also psychomotor effects of cocaine on activity; however, the contributions of each signaling pathway are unknown. Chapter 3 examined the creation of a cell-type specific herpes simplex viral (HSV) vector system to over-express wildtype TrkB or its docking mutants. In vivo and cell culture experiments indicated very weak viral expression, while cocaine self-administration testing produced inconsistent and inconclusive results. Chapter 4 examined cocaine-induced BDNF-TrkB receptor signaling using an adeno-associated viral vector system to over-express wildtype TrkB and its signaling mutants, more generally across NAc cell types. Initial self-administration testing suggested that overexpression of kinase dead TrkB (TrkB K571N) in the NAc shell increased the threshold dose required to maintain self-administration on the dose-response test and reduced motivation for cocaine. Subsequent behavioral testing did not confirm these results. Preliminary tissue staining demonstrated similar levels of viral infectivity between AAV-GFP and AAV-TrkB WT; however, subsequent tissue staining demonstrated very weak to no viral expression, consistent with the lack of consistent behavioral results. Finally, Chapter 5 utilized a transient but efficacious HSV vector system to over-express wildtype TrkB and its signaling mutants during cocaine-induced activation of the BDNF-TrkB receptor signaling pathway. Self-administration testing suggested that the kinase dead TrkB viral mutant (HSV-TrkB K571N) inversely affected cocaine taking and motivation for cocaine. In contrast to the cell-specific HSV vectors tested earlier, immunohistochemical techniques indicated stronger and consistent expression of these HSV-TrkB viruses; however, TrkB signaling-specific protein expression was not found. These findings indicate an inconsistency between behavioral results and viral expression, yet suggest that further experimentation is warranted."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Role of BDNF-TrkB Signaling in Cocaine Addiction"]}]}],"canonical_facts":{"dc:contributor":["Goldberg, Matthew S.","Monteggia, Lisa","Rothenfluh, Adrian","Self, David W."],"dc:creator":["Buzin, Nicole Renee"],"dc:date":["2016-06-27T20:02:39Z","2014-05","2014-04-14","May 2014","2016-06-27T19:48:27Z"],"dc:description":["Cocaine addiction results in neuroadaptations and drug-induced neuroplasticity that promote changes in protein expression and neuron morphology. Cocaine-induced increases in dopamine ultimately alter dopamine signaling in brain regions modulating reward and motivation, specifically the nucleus accumbens (NAc), and downstream proteins. One protein of particular interest is brain-derived neurotrophic factor (BDNF), a modulator of cell survival, viability, and plasticity. Cocaine has been shown to increase BDNF mRNA and protein levels in the NAc shell. In addition, intra-NAc infusions of BDNF have been demonstrated to increase cocaine intake and motivation for cocaine. These increases in BDNF also lead to activation of its receptor, tropomyosin receptor kinase B (TrkB). Studies indicate that the loss of TrkB specifically in the NAc shell reduced the reinforcing effects of cocaine using a self-administration paradigm, and also psychomotor effects of cocaine on activity; however, the contributions of each signaling pathway are unknown. Chapter 3 examined the creation of a cell-type specific herpes simplex viral (HSV) vector system to over-express wildtype TrkB or its docking mutants. In vivo and cell culture experiments indicated very weak viral expression, while cocaine self-administration testing produced inconsistent and inconclusive results. Chapter 4 examined cocaine-induced BDNF-TrkB receptor signaling using an adeno-associated viral vector system to over-express wildtype TrkB and its signaling mutants, more generally across NAc cell types. Initial self-administration testing suggested that overexpression of kinase dead TrkB (TrkB K571N) in the NAc shell increased the threshold dose required to maintain self-administration on the dose-response test and reduced motivation for cocaine. Subsequent behavioral testing did not confirm these results. Preliminary tissue staining demonstrated similar levels of viral infectivity between AAV-GFP and AAV-TrkB WT; however, subsequent tissue staining demonstrated very weak to no viral expression, consistent with the lack of consistent behavioral results. Finally, Chapter 5 utilized a transient but efficacious HSV vector system to over-express wildtype TrkB and its signaling mutants during cocaine-induced activation of the BDNF-TrkB receptor signaling pathway. Self-administration testing suggested that the kinase dead TrkB viral mutant (HSV-TrkB K571N) inversely affected cocaine taking and motivation for cocaine. In contrast to the cell-specific HSV vectors tested earlier, immunohistochemical techniques indicated stronger and consistent expression of these HSV-TrkB viruses; however, TrkB signaling-specific protein expression was not found. These findings indicate an inconsistency between behavioral results and viral expression, yet suggest that further experimentation is warranted."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/3306","952355655"],"dc:language":["en_US"],"dc:subject":["Brain-Derived Neurotrophic Factor","Cocaine-Related Disorders","Nucleus Accumbens","Receptor, trkB"],"dc:title":["Role of BDNF-TrkB Signaling in Cocaine Addiction"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:13Z"}