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Abstract

With the number of opioid-related deaths continuing to rise, the demand for an effective treatment for opioid use disorder is growing. Despite the emotional symptoms of withdrawal, termed hyperkatifeia, being a strong predictor of relapse, there is little understanding as to the mechanisms responsible for producing hyperkatifeia. This thesis examines the role of the anterior cingulate cortex (ACC) in the production of hyperkatifeia. The aim of this thesis was to identify a potential mechanism for producing hyperkatifeia, which could provide a target for future treatments. I first found that electrolytic lesion of the ACC abolished physical and emotional symptoms of withdrawal, measured with the Von Frey test and a conditioned place aversion test, respectively. These results suggest that the ACC is involved in the production of hyperkatifeia, warranting further investigation of this region. Next, I measured dopamine efflux in the ACC using fiber photometry paired with the dopamine sensor GRABDA3h. I found that dopamine in the medial frontal cortex does not encode reward predictor errors. Moreover, our results suggested that instead dopamine functions as an arousal signal and provide support for the dual-state theory. Finally, I found that during opioid withdrawal the dopamine response to emotionally salient events is altered. Specifically, I observed a greater phasic dopamine response to salient events during withdrawal. These elevations in dopamine would affect the ensemble representations which project to downstream regions involved in producing emotional and autonomic responses. We believe hyperkatifeia is the result of these increased phasic dopamine responses.