Dysregulation of glutamatergic signaling mechanisms is a component of many psychiatric diseases. A number of these diseases exhibit a bias toward one sex, yet the ways in which glutamate is affected by or modulates this bias is poorly understood. In cocaine addiction, women progress from initial use of the drug to substance use disorder faster than men, and have more difficulty remaining abstinent. The same is true in female rodents. We used a mouse model of cocaine self-administration to study the role of glutamate receptor trafficking proteins in cocaine addiction-like behavior in males and females. In the first set of experiments, mice received a conditional knockout of glutamate receptor interacting protein 1 (GRIP1) in the medial prefrontal cortex (mPFC). This led to an increase in motivation for cocaine as well as enhanced likelihood of relapse behavior, as measured by a progressive ratio schedule and cue-induced reinstatement, respectively. No sex differences were seen after prefrontal deletion of GRIP1. The next set of experiments used the same behavioral paradigm, but mice received a conditional knockout of protein interacting with C kinase 1 (PICK1) in the mPFC. PICK1 and GRIP1 are both involved in the activity dependent trafficking of the GluA2-containing AMPA receptor, but while GRIP1 maintains these receptors in the synapse, PICK1 internalizes them in response to a stimulus such as drug experience. The prefrontal deletion of PICK1 was predicted to decrease cue-reinstatement responding, and this was observed in the male mice. The female mice displayed an increase in cue-induced reinstatement responding, similar to the effects seen by prefrontal GRIP1 deletion. Sex differences in PICK1 have not previously been described in the literature. Our results suggest that PICK1 is involved in different baseline processes in females, and merit further study. The final set of experiments considered the interaction of gonadal hormones and PICK1 in males. Bilateral gonadectomy or sham surgery was combined with prefrontal PICK1 knockout to determine if circulating gonadal hormones could explain the results in males. After gonadectomy or sham surgery, there was no significant effect of prefrontal PICK1 deletion on cue-induced reinstatement. These results do not fully explain the sex difference observed in intact mice. Together, these studies suggest that baseline sex differences exist in PICK1-mediated mechanisms of cocaine reinstatement and that these differences are not due to the influence of gonadal hormones alone. / Psychology
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/4030 |
| Date | January 2020 |
| Creators | Wickens, Megan Marie |
| Contributors | Briand, Lisa A., Bangasser, Debra A., Parikh, Vinay, Wimmer, Mathieu, Murty, Vishnu, Rawls, Scott M. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 116 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/4012, Theses and Dissertations |
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