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Dissertation
The effects of dual hypocretin/orexin receptor blockade on oxycodone seeking and dopamine neurotransmission in the nucleus accumbens
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2023
DOI:
https://doi.org/10.17918/00001644
Abstract
The opioid epidemic has been ongoing for decades and has impacted millions of lives. Although there are approved pharmacotherapies to treat opioid use disorder (OUD), they continue to fall short of mitigating the opioid crisis. One of the primary challenges in treating OUD is that attempted opioid-abstinence is plagued by extremely high rates of relapse. Drug craving is one of the most potent influences in driving relapse, and thus, remains an attractive target for future treatments. The underpinnings of drug craving are not completely understood, but a substantial body of work implicates dopamine in the mesolimbic pathway as being integral for drug-associated behaviors, such as drug craving. Further, the hypocretin system has recently emerged as potentially promising novel treatment for OUD, as evidence has widely supported hypocretin-based treatments in reducing motivated behaviors by way of modulating dopamine transmission. The overarching goal of this work is to investigate the state of dopamine system in the nucleus accumbens during opioid abstinence, assess how a dual hypocretin receptor antagonist, suvorexant, can reduce opioid craving, and determine if the mechanism is through normalization of aberrant dopamine transmission. To do this, rats self-administered oxycodone for 10 days under an intermittent access schedule, paired with cue-induced craving tests on abstinence day (AD) 1 and AD14, rats were sacrificed on AD2 or AD15 to measure dopamine transmission using fast-scan cyclic voltammetry. I found that rats exhibited robust persistent oxycodone seeking during abstinence and this coincided with reductions in dopamine uptake on AD2 and AD15. Next, rats underwent the same oxycodone self-administration followed by a seeking test on AD14 but were treated with vehicle or suvorexant 24 hours before the seeking test, and rats were sacrificed for FSCV on AD15. I found that suvorexant attenuated oxycodone craving behavior, with the effect being more prominent in males, and normalized dopamine uptake in the NAc. This provides additional support for the potential use of hypocretin-agents for the treatment of OUD.
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Details
- Title
- The effects of dual hypocretin/orexin receptor blockade on oxycodone seeking and dopamine neurotransmission in the nucleus accumbens
- Creators
- Kyle Samson
- Contributors
- Rodrigo A. España (Advisor)Sandhya Kortagere (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xi, 182 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 991020504713904721