The present thesis examined the potential interaction between postingestive cues and the dopamine antagonist pimozide on the inhibition of sucrose sham intake. Coadministration of CCK and pimozide IP produced additive inhibitory effects on sham feeding of 4% or 17.1% sucrose. Manipulations of blood glucose levels by infusion of 10% dextrose or injection of 0.1U insulin SC did not interact with pimozide to alter the latter drug's inhibition of 34.2% sucrose sham feeding. Separate experiments verified that these manipulations significantly altered blood glucose levels compared to a control 0.9% saline infusion IV. Infusions of d-glucose into the lateral ventricle significantly enhanced the inhibitory effects of pimozide on 34.2% sucrose sham intake compared to infusions of!glucose or 2-deoxy-glucose. Infusions of d-glucose into the third ventricle, however, significantly attenuated the inhibitory effects of pimozide on 34.2% sucrose sham feeding compared to the control l-glucose infusions. These results collectively suggest that some postingestive cues, such as elevations in third ventricle glucose levels, are indeed capable of inhibiting the suppressive effects of pimozide on sucrose sham feeding. / Thesis / Master of Science (MSc)

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Simple Summary Glioblastoma is the most common primary brain cancer in adults. One reason for the development and malignancy of this tumor is the misregulation of certain cellular proteins. The oncoprotein STAT3 that is frequently overactive in glioblastoma cells is associated with more aggressive disease and decreased patient survival. Autophagy is a form of cellular self digestion that normally maintains cell integrity and provides nutrients and basic building blocks required for growth. While glioblastoma is known to be particularly resistant to conventional therapies, recent research has suggested that these tumors are more sensitive to excessive overactivation of autophagy, leading to autophagy-dependent tumor cell death. Here, we show a hitherto unknown role of STAT3 in sensitizing glioblastoma cells to excessive autophagy induced with the repurposed drug pimozide. These findings provide the basis for future research aimed at determining whether STAT3 can serve as a predictor for autophagy-proficient tumors and further support the notion of overactivating autophagy for cancer therapy. Abstract Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings suggest that the antipsychotic drug pimozide triggers an autophagy-dependent, lysosomal type of cell death in GBM cells with possible implications for GBM therapy. One oncoprotein that is often overactivated in these tumors and associated with a particularly dismal prognosis is Signal Transducer and Activator of Transcription 3 (STAT3). Here, we used isogenic human and murine GBM knockout cell lines, advanced fluorescence microscopy, transcriptomic analysis and FACS-based assessment of cell viability to show that STAT3 has an underappreciated, context-dependent role in drug-induced cell death. Specifically, we demonstrate that depletion of STAT3 significantly enhances cell survival after treatment with Pimozide, suggesting that STAT3 confers a particular vulnerability to GBM. Furthermore, we show that active STAT3 has no major influence on the early steps of the autophagy pathway, but exacerbates drug-induced lysosomal membrane permeabilization (LMP) and release of cathepsins into the cytosol. Collectively, our findings support the concept of exploiting the pro-death functions of autophagy and LMP for GBM therapy and to further determine whether STAT3 can be employed as a treatment predictor for highly apoptosis-resistant, but autophagy-proficient cancers.