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Dissertation
Hypocretin receptor 1 modulations on specific neuronal subtypes in the ventral tegmental area impact mesolimbic dopamine and cocaine-associated behavior
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2021
DOI:
https://doi.org/10.17918/00000857
Abstract
There are currently no approved pharmacotherapies for treating cocaine use disorder. However, the hypocretin system, particularly hypocretin receptor 1 (HCRTr1) which acts on mesolimbic dopamine (DA), seems to be a promising therapeutic target. In this thesis I utilize a novel combinatorial viral approach to selectively knockdown HCRTr1 on DA or GABA neurons in the ventral tegmental area (VTA). I characterize this viral knockdown with infusion confirmations and qRT-PCR. I then use fast scan cyclic voltammetry to examine the effects of HCRTr1 knockdown on VTA DA vs GABA neurons on DA dynamics in the nucleus accumbens (NAc). I also use cocaine self-administration behavioral schedules of reinforcement to examine how different aspects of cocaine taking are impacted by this knockdown. Results from the present study indicate that knockdown of HCRTr1 on VTA DA neurons significantly reduces HCRTr1 mRNA in the VTA, reduces DA sensitivity to cocaine in the NAc, and reduces motivation to self-administer cocaine. Interestingly, HCRTr1 knockdown of HCRTr1 on VTA GABA neurons significantly reduces HCRTr1 mRNA in the VTA, enhances DA sensitivity to cocaine in the NAc, and does not affect cocaine self-administration behavior. Though complex, the findings from the present study set a precedent for investigation of differential neuronal subtypes in the VTA and lead the way for future studies as well as development of improved pharmacotherapies for cocaine use disorder.
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Details
- Title
- Hypocretin receptor 1 modulations on specific neuronal subtypes in the ventral tegmental area impact mesolimbic dopamine and cocaine-associated behavior
- Creators
- Emily Marie Black
- Contributors
- Ramesh Raghupathi (Advisor)Rodrigo A. España (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- ix, 145 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 991015473792504721