Role of BDNF-TrkB Signaling in Cocaine Addiction
Buzin, Nicole Renee
MetadataShow full item record
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.