EcoHIV infection effects on cocaine seeking and neuroimmune responses in male mice depend on cocaine exposure pattern.

Cocaine use disorders (CUDs) and human immunodeficiency virus (HIV) remain persistent public health dilemmas throughout the world. Cocaine seeking increases over a protracted period of abstinence, an effect known as the incubation of craving. Little is known about how HIV may modulate this process. Thus, we sought to examine the impact of chronic HIV infection on the incubation of cocaine craving and associated changes in the expression levels of central neuroimmune and peripheral immune substrates. Here, male mice were inoculated with EcoHIV, which is a chimeric HIV-1 construct that produces chronic HIV infection in mice. Mice were conditioned with cocaine daily or intermittently in a conditioned place preference (CPP) paradigm, followed by 1 or 21 days of forced abstinence prior to assessing preference for the cocaine-paired chamber. Mice conditioned daily exhibited potentiated incubation of cocaine CPP after 21 days of abstinence, and EcoHIV increased cocaine CPP across the test session at both abstinence timepoints. Conversely, EcoHIV-infected mice conditioned intermittently showed higher cocaine seeking after 1 day of abstinence compared to 21 days. Analysis of corticolimbic CX3CL1-CX3CR1 and glutamate receptor expression revealed a positive relationship between cocaine seeking and medial prefrontal cortex (mPFC) CX3CL1 and GluA1, as well as a nucleus accumbens (NAc) GluN2A expression. Moreover, examination of peripheral immune markers showed that the effect of abstinence and EcoHIV infection on these measures depended on the cocaine exposure regimen. Altogether, these results highlight the importance of cocaine abstinence and exposure pattern as critical variables that modulate HIV-associated neuroimmune outcomes and relapse vulnerability.