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Cross-model investigation on the role of inflammasomes in the neurobehavioral and transcriptomic effects of cocaine exposure and HIV infection

Award Number: R01DA062277
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Cross-model investigation on the role of inflammasomes in the neurobehavioral and transcriptomic effects of cocaine exposure and HIV infection - Cocaine use disorder (CUD) is a highly prevalent in people living with HIV (PWH), and co-occurring HIV and CUD result in poorer clinical outcomes and more severe neurocognitive sequelae. Despite exacerbated risk for behavioral and cognitive deficits in PWH who use cocaine, there is limited understanding and an absence of targeted therapeutic strategies addressing the effects of CUD and HIV on the brain. Better definition of the interaction between cocaine use and HIV infection in the CNS is essential to address this knowledge gap. HIV and CUD both increase neuroinflammation via activation of inflammasomes, multiprotein complexes that regulate inflammation through production of the cytokines IL-1β and IL-18. NLRP3, the most widely studied inflammasome, is highly expressed in microglia, as well as other CNS myeloid cells. Cocaine exposure and HIV infection can both activate NLRP3. While processes regulating inflammasome activity are well-defined, the mechanisms by which HIV and cocaine affect them are not. Cocaine increases dopamine in the mesolimbic region. Increased dopamine appears to mediate the effects of cocaine effects on inflammasomes, as cocaine use upregulates NLRP3 expression and IL-1β in the mesolimbic region in vivo (when it increases dopamine levels), but not in microglia in vitro. HIV infection also disrupts dopamine reuptake and metabolism and increases inflammation in mesolimbic structures. This suggests that cocaine use and HIV infection interact via dopaminergic dysregulation, potentiating regional neuroinflammation and disrupting behaviors and cognitive processes defined by mesolimbic circuits. The mechanistic link between dopamine and inflammasomes is not clear, but mitochondrial dysregulation has been shown to regulate inflammasome activity in myeloid cells. Our preliminary data show that dopamine increases NLRP3 activity in human iPSC-derived microglia in vitro, and that in human macrophages, dopamine specifically enhances caspase expression and Gasdermin cleavage. In these human macrophages, dopamine also disrupts mitochondrial fission, and blocking the effects of dopamine on mitochondrial fission inhibits the dopamine-enhanced in inflammasome activity. We also show that HIV and cocaine interact to drive inflammation and disrupt reward-seeking behavior in vivo in EcoHIV-infected mice self- administering cocaine, which correlates with other studies showing that cocaine mediated inflammation impairs drug seeking behavior and cognitive function. Thus, we hypothesize that cocaine-mediated increases in dopamine potentiate inflammasome activation in microglia in the HIV-infected CNS by dysregulating mitochondria and enhancing neuroinflammation, which contributes to cognitive deficits and aberrant reward seeking. Our proposal addresses this hypothesis in in vitro, ex vivo and in vivo models at the single cell (Aim 1), circuit and behavioral (Aim 2) levels. This will generate of data from complementary human and rodent systems to overcome the limitations inherent in any single neuroHIV model and generate interconnected data sets correlating functional, and behavioral changes in response to HIV and cocaine use.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $684,123 )
2026	2026	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	1	3/4/2026	NEW	$684,123
														Subtotal = $684,123

Grand Total All Awards = $684,123

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Cross-model investigation on the role of inflammasomes in the neurobehavioral and transcriptomic effects of cocaine exposure and HIV infection

Award Number: R01DA062277

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/15/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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