Dissertation
Targeting hypocretin receptor 1 to normalize nucleus accumbens dopamine transmission and block incubation of cocaine seeking
Doctor of Philosophy (Ph.D.), Drexel University
Oct 2022
DOI:
https://doi.org/10.17918/00001397
Abstract
Cocaine use disorder is a devastating condition for which there are no approved pharmacotherapies. A robust body of work indicates that Nucleus Accumbens (NAc) dopamine (DA) transmission is highly dysregulated following chronic cocaine use. Unfortunately, therapeutics that directly modulate DA transmission tend to carry intolerable side-effects and have a high abuse liability, invalidating their use in clinical populations. However, a growing body of evidence indicates that Hypocretin/Orexin system (HCRT) may be a promising target for therapeutics. Work from our lab indicates that treatment with a HCRT Receptor 1 (HCRTr1) antagonist can lower cocaine intake and reduce cocaine's effect on DA transmission. Although it remains unclear whether HCRTr1 can also reduce the risk of relapse during abstinence from cocaine. In the present studies, we implement a model of relapse to cocaine seeking in which animals self-administer cocaine on the Intermittent Access schedule for one week, followed by one week of forced abstinence (IntA + Abstinence). Using this model, cue-induced seeking tests on abstinence day 1 (AD1) and abstinence day 8 (AD8) revealed an increase, or incubation, of cue-induced drug seeking that is consistent with high drug craving. Furthermore, these animals exhibited dysregulated NAc DA transmission and increased phosphorylation of the dopamine transporter (DAT). We then tested whether the HCRTr1 antagonist, RTIOX-276, could block the incubation of cocaine seeking and prevent aberrant effects on NAc DA transmission. We found that a single dose of RTIOX-276 delivered on the first day of abstinence blocked incubation of cocaine seeking, suggesting it lowered cocaine cravings. Furthermore, animals that were treated with RTIOX-276 did not exhibit abnormal NAc DA transmission or DAT biochemistry. We therefore posit that HCRTr1 may serve as a valuable therapeutic target to reduce relapse rates and normalize NAc DA transmission in those suffering from cocaine use disorder.
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Details
- Title
- Targeting hypocretin receptor 1 to normalize nucleus accumbens dopamine transmission and block incubation of cocaine seeking
- Creators
- Philip J. Clark
- Contributors
- Rodrigo A. España (Advisor)Kimberly J. Dougherty (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 173 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 991019300413504721