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Dissertation
Inherent individual differences in presynaptic dopamine dynamics govern cocaine-associated behavior
Doctor of Philosophy (Ph.D.), Drexel University
Oct 2018
DOI:
https://doi.org/10.17918/hpp4-7642
Abstract
Cocaine addiction is a chronic, relapsing disease characterized by the heavy use of, aberrant motivation for, and an inability to maintain abstinence from cocaine. Considerable effort has been directed towards understanding the factors underlying the risk for cocaine addiction; however, the mechanisms that predispose individuals to develop the disease remain unclear. The mesolimbic dopamine system has been particularly implicated in the reinforcing effects of cocaine, which enhances extracellular dopamine in this system primarily by inhibiting dopamine uptake. Recent evidence suggests that inherent variability in dopamine neurotransmission may influence the risk for developing cocaine addiction. To determine the relative contributions of dopamine release and uptake to the vulnerability to use cocaine, we first employed a novel application of fast scan cyclic voltammetry in anesthetized male rats to construct a neurochemical profile of DA signaling in the medial dorsal striatum (mDS) and ventral striatum of individual animals under baseline, drug-naïve conditions-prior to any behavioral testing. Following recovery, rats were either allowed to self-administer cocaine or were induced to develop cocaine conditioned place preference (CPP). Results suggest that there is no significant relationship between dopamine release or uptake and the acquisition of either CPP or operant self-administration, nor did we identify a significant relationship between dopamine signaling and the consumption of cocaine. We did, however, identify a strong, linear relationship between dopamine uptake in the mDS and the motivation for cocaine under progressive ratio and threshold schedules of reinforcement as well as cocaine-primed reinstatement-implicating DAT function in the risk for aberrant motivation associated with cocaine addiction. Moreover, results using ex vivo voltammetry suggest that inherent variability in dopamine uptake mediates the neurochemical sensitivity to cocaine, suggesting that faster rates of uptake may enhance the interoceptive properties of cocaine. Finally, preliminary results using viral manipulations to reduce DA uptake further suggest that DA uptake governs motivation for cocaine. Together, these data suggest that inherent variability in the mesolimbic dopamine system may underlie behavioral components associated with cocaine abuse.
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Details
- Title
- Inherent individual differences in presynaptic dopamine dynamics govern cocaine-associated behavior
- Creators
- Jessica Kaytlin Shaw - DU
- Contributors
- Rodrigo A. España (Advisor) - Drexel University (1970-)Ramesh Raghupathi (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xii, 199 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 8860; 991014632286204721