Astrocytic HIV-1 Nef expression decreases glutamate transporter expression in the nucleus accumbens and increases cocaine-seeking behavior in rats
Cocaine use disorder is an intersecting issue in populations with HIV-1, further exacerbating the clinical course of the disease, contributing to neurotoxicity and neuroin-flammation. Cocaine and HIV neurotoxins play roles in neuronal damage during neuroHIV progression by disrupting glutamate homeostasis in the brain. Even with cART, HIV-1 Nef, an early viral protein expressed in approximately 1% of infected astrocytes, remains a key neurotoxin. This study investigates the relationship that exists between Nef, glutamate homeostasis, and cocaine in the NAc, a critical brain region associated with drug motiva-tion and reward. Using a rat model, we compared the effects of astrocytic Nef and cocaine by molecular analysis of glutamate transporters in the NAc. We further conducted be-havioral assessments for cocaine self-administration to evaluate cocaine-seeking behavior. Our findings indicate that both cocaine and Nef independently decrease the expression of the glutamate transporter GLT-1 in the NAc. Additionally, rats with astrocytic Nef ex-pression exhibited increased cocaine-seeking behavior but demonstrated sex dependent molecular differences after behavioral paradigm. In conclusion, our results suggest the expression of Nef intensifies cocaine-induced alterations in glutamate homeostasis in the NAc, potentially underlying increased cocaine-seeking. Understanding these interactions better may inform therapeutic strategies for managing cocaine use disorder in HIV-infected individuals.