Background: Alcohol use disorders are characterized by inflexible alcohol seeking that occurs despite adverse consequences. Males and females are differentially sensitive to ethanol (EtOH) reward, but it is unclear whether sex differences in EtOH seeking under reward-aversion conflict are present.Methods: To investigate sex differences in EtOH seeking under conflict, adult male and female C57BL/6J mice underwent chronic intermittent EtOH (CIE) exposure by vapor inhalation or served as air-exposed controls. After CIE, mice were trained in a modified EtOH conditioned place preference paradigm. During 3 conditioning sessions, 2 g/kg EtOH was administered prior to confinement in the "EtOH-paired" chamber. On alternating days, saline was injected prior to confinement in the "salinepaired" chamber. After conditioning, mice experienced a footshock in the EtOH-paired chamber. EtOH-seeking behavior was assessed before and after footshock.Results: Control and CIE-exposed males reduced the time spent in and increased latency to enter the reward-paired chamber following footshock. Control females did not alter EtOH-seeking behavior following footshock. CIE-exposed females spent more time in the EtOH-paired chamber at baseline. However, following a footshock, CIE-exposed females significantly reduced the time spent in and increased latency to enter the EtOH-paired chamber.Conclusions: Nondependent female mice exhibited aversion-resistant alcohol seeking to a greater degree than males. Chronic EtOH exposure did not impact EtOH seeking in males. In females, CIE enhanced EtOH seeking in the absence of conflict, but reduced EtOH seeking after an aversive experience. While these sex-specific effects of CIE are not present when reward seeking is assessed in the absence of an aversive experience, multiple factors may underlie the differences in reward seeking despite adverse consequences, including reward-and aversion-related learning and decision making under conflict. These data highlight the importance of considering sex as a variable influencing EtOH seeking and provide a greater understanding of how sex interacts with EtOH exposure to alter behavior.

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Background Substance use disorders (SUDs) are characterized by high propensity to relapse and are highly comorbid with HIV infection. The underlying neurobiology of this relationship is poorly understood. Preclinical research on the neurobiobehavioral outcomes of progressive HIV infections may yield crucial information to improve SUD prognosis and reduce risk of relapse in people living with HIV. Methods To model progressive HIV, adult male and female C57BL6J mice were inoculated with EcoHIV, a chimeric HIV‐1 which infects murine cells by replacing envelope glycoprotein gp120 with gp80. Five weeks after inoculation mice were trained in a cocaine conditioned place preference (CPP) paradigm (10mg/kg, i.p.) followed by extinction training. Stress‐induced reinstatement was assessed following administration of yohimbine, an α2 adrenergic antagonist, to determine EcoHIV effects. Neuronal activation in the prefrontal cortex (PFC) and nucleus accumbens (NAc) by cocaine exposure was assessed by quantitative analysis the expression of the immediate early gene, cFos. Results EcoHIV and sham‐inoculated mice exhibited similar cocaine CPP and extinction. However, EcoHIV mice showed significantly increased yohimbine‐induced reinstatement rate (p<0.05). cFos analysis revealed an elevated neural activation in PFC and NAc in response to cocaine. However, only neurons within infralimbic PFC (IL) and NAc shell subregions showed further increases in activity in cocaine exposed mice infected with EcoHIV vs shams. Conclusion EcoHIV infected mice escalated stress‐induced reinstatement of cocaine seeking compared to controls, suggesting that people living with HIV may be at elevated risk for stress‐induced relapse. Progressive EcoHIV infection may dysregulate IL and NAcShell activity to facilitate the cocaine seeking and reinstatement. Ongoing research will characterize how EcoHIV infection dysregulate IL‐NAcShell pathway specific activity during cocaine reward learning and stress‐induced relapse.

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