Role of BDNF-TrkB Signaling in Cocaine Addiction
| dc.contributor.advisor | Goldberg, Matthew S. | en |
| dc.contributor.committeeMember | Monteggia, Lisa | en |
| dc.contributor.committeeMember | Rothenfluh, Adrian | en |
| dc.contributor.committeeMember | Self, David W. | en |
| dc.creator | Buzin, Nicole Renee | en |
| dc.date.accessioned | 2016-06-27T20:02:39Z | |
| dc.date.available | 2016-06-27T20:02:39Z | |
| dc.date.created | 2014-05 | |
| dc.date.issued | 2014-04-14 | |
| dc.date.submitted | May 2014 | |
| dc.date.updated | 2016-06-27T19:48:27Z | |
| dc.description.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. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 952355655 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/3306 | |
| dc.language.iso | en_US | en |
| dc.subject | Brain-Derived Neurotrophic Factor | en |
| dc.subject | Cocaine-Related Disorders | en |
| dc.subject | Nucleus Accumbens | en |
| dc.subject | Receptor, trkB | en |
| dc.title | Role of BDNF-TrkB Signaling in Cocaine Addiction | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Neuroscience | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |