The development of anxiety and mood disorders often coincides with exposure to stress. Accumulating evidence indicates that both corticotropin-releasing factor (CRF) and dynorphin, the endogenous ligand for the kappa-opioid receptor (KOR), can mediate the effects of stress. My dissertation research utilized laboratory animals to investigate the role of KORs in stress-induced increases in the acoustic startle response, a metric often used to study stress effects in humans. Using wild-type mice, I first demonstrated that systemic administration of a KOR antagonist produced an anxiolytic-like effect on acoustic startle following central (intracerebroventricular) infusion of CRF. Immunohistochemical analysis revealed that KOR blockade decreased c-Fos cell counts in the dentate gyrus of the hippocampus in both vehicle- and CRF-treated mice, and reduced CRF-induced increases in the ventral tegmental area (VTA). Within the VTA, reductions were predominantly in dopaminergic neurons. KOR antagonist pretreatment also produced anxiolytic-like effects on footshock-potentiated startle, a model that quantifies context-specific fear conditioning. To complement the antagonist studies, we developed constitutive knockout mice that lack KORs throughout the brain (KOR-/-), and conditional KOs that lack KORs only within dopaminergic neurons (DAT-KORlox/lox). Initial characterization demonstrated that these two mutant lines did not differ from controls in hearing, vision, weight gain, and locomotor activity. KOR-/- mice were similar to controls in unconditioned anxiety-like behavior, but DAT-KORlox/lox mice displayed nominal decreases in anxiety-like behavior in the open field and light/dark box. Unexpectedly, KOR ablation did not affect CRF-induced increases in startle in either mutant line. Importantly, however, KOR antagonist treatment did not alter CRF-induced increases in startle in KOR-/- mice, suggesting that KOR antagonist effects in wild-type mice are due to blockade of KORs. These findings raise the possibility that differences in KOR antagonist and KOR-/- studies may be related to brief KOR blockade during adulthood versus a lack of KORs during the entire lifespan. In the footshock-potentiated startle paradigm, KOR-/- mice were comparable to littermate controls, whereas DAT-KORlox/lox mice showed attenuated effects of footshock. My findings confirm a role for KORs in fear and anxiety-like behavior in rodents, and implicate KORs expressed on dopaminergic neurons in modulating important aspects of stress-related behavior.
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/11151536 |
| Date | 08 October 2013 |
| Creators | Van't Veer, Ashlee Victoria |
| Contributors | Carlezon, Willaim, Hensch, Takao K |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Rights | open |
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