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Dissertation
The impact of EcoHIV infection on cocaine-related behaviors
Doctor of Philosophy (Ph.D.), Drexel University
Oct 2024
DOI:
https://doi.org/10.17918/00010806
Abstract
Cocaine use disorder (CUD) is highly comorbid with HIV infection and worsens HIV outcomes. Preclinical research on the outcomes of HIV infection may yield crucial information on neurobehavioral changes resulting from chronic drug exposure in people living with HIV (PLWH). HIV infection can produce profound neurobiological and behavioral changes that impact reward neuronal substrates that overlap with cocaine exposure. The nucleus accumbens (NAc) is a key mediator of cocaine-related behaviors, including cocaine locomotor sensitization, cocaine reward learning, and relapse-related behavior. Both the NAc and its afferent projection from the medial prefrontal cortex (mPFC) appear to be particularly sensitive to cocaine and EcoHIV infection, contributing to neuroinflammation and neuronal adaptations. These alterations may increase susceptibility to CUD in PLWH. Thus, the broad objective of my thesis work was to characterize the independent and interactive effects of cocaine and HIV infection on neurobiological and behavioral changes. Using the EcoHIV mouse model, a chimeric form of HIV-1 that infects rodents, I investigated the impact of HIV infection on neuronal substrates of addiction and on cocaine-related behaviors. I found that EcoHIV induced a heightened neuroimmune response in the NAc, associated with altered microglia-neuron signaling, that was not reversed by antiretroviral treatment. Additionally, EcoHIV infection enhanced cocaine-primed reinstatement, a model of relapse-related behavior. This phenomenon is linked to neuroplasticity in the infralimbic (IL) subregion of the mPFC and the NAc shell. Thus, we further demonstrated that chemogenetic activation of this circuit reversed the increased cocaine-primed reinstatement caused by EcoHIV. These findings suggest that HIV infection disrupts the mPFC-NAc shell circuit, and enhancing its activity inhibit relapse-related behaviors. As NAc astrocytes are key regulators of neural activity and plasticity, and their function can be impaired by cocaine exposure and HIV infection, they are potential regulators of HIV-induced changes in behavioral response to cocaine. I used a cocaine locomotor sensitization model to examine how HIV infection affects neuroadaptations and behavioral plasticity. EcoHIV infection potentiated cocaine sensitization, which was further associated with increased astrocytic activation in the NAcore. Chemogenetic activation of NAc astrocyte Gq signaling attenuated the EcoHIV-enhanced sensitization, suggesting that promoting NAc astrocytic Gq signaling can reverse EcoHIV-induced behavioral changes. Overall, these results suggest that EcoHIV infection dysregulates neuroimmune signaling and induces neuronal adaptations in reward-related regions, driving changes in cocaine-related behaviors. Given the high rates of comorbid CUD and HIV infection, my thesis provides insights into the development of novel approaches to mitigate addiction-related behaviors and neurocognitive outcomes in PLWH with CUD.
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Details
- Title
- The impact of EcoHIV infection on cocaine-related behaviors
- Creators
- Qiaowei Xie
- Contributors
- Jacqueline M. Barker (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- ix, 144 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991022019119004721