Sex differences in neuronal activation during aversion-resistant alcohol consumption.

BACKGROUND: One of the DSM-5 criteria for Alcohol Use Disorder is continued alcohol consumption despite negative consequences. This has been modeled in mice using adulteration of alcohol solution with the bitter tastant quinine. Mice that continue to consume alcohol despite this adulteration are considered aversion resistant. The limited number of studies dissecting the underlying neuronal mechanisms of aversion-resistant drinking behaviors used only male subjects. We have previously shown that female mice are more resistant to quinine adulteration of alcohol than males. Our aim here is to identify potential sex differences in neuronal activation that may underlie this behavior. METHODS: Male and female C57BL/6J mice were allowed continuous access to 20% alcohol in a two-bottle choice procedure. To test aversion-resistance, the alcohol was adulterated with increasing concentrations (0.03, 0.1, and 0.2 mM) of quinine hydrochloride. After consumption rates were calculated, brains were extracted to examine neuronal activation using Fos immunohistochemistry. RESULTS: We found that female mice suppressed their intake to a lesser extent than males when the alcohol solution was adulterated with quinine. Our Fos staining revealed three regions of interest that exhibit a sex difference during quinine-adulterated alcohol drinking: the ventromedial prefrontal cortex (vmPFC), the posterior insular cortex (PIC), and the ventral tegmental area (VTA). Both the vmPFC and the PIC exhibited higher neuronal activation in males during quinine-adulterated alcohol consumption. However, females showed higher Fos activation in the VTA during quinine-adulterated alcohol consumption. CONCLUSIONS: Females more readily exhibit aversion-resistant alcohol intake than their male counterparts and exhibit some differences in neuronal activation patterns. We conclude that there are sex differences in neurocircuitry that may underlie compulsive drinking behaviors.

The effect of concurrent access to alcohol and oxycodone on self-administration and reinstatement in rats.

RATIONALE: Although polysubstance use is highly prevalent, preclinical studies that assess voluntary consumption of multiple substances at the same time are rather uncommon. Overlooking drug taking patterns commonly observed in humans may limit the translational value of preclinical models. OBJECTIVES: Here, we aimed to develop a model of polysubstance use that could be used to assess oral operant self-administration patterns under concurrent access to alcohol and the prescription opioid oxycodone. METHODS: After a training period where animals associated specific cues and levers with each drug, rats self-administered alcohol and oxycodone solutions concurrently in daily sessions. Oxycodone was then removed to assess potential changes in alcohol consumption. The role of cues and stress on alcohol consumption and oxycodone seeking was also examined under reinstatement conditions. RESULTS: We found that females consumed more alcohol and oxycodone than males when given access to both drugs, and this effect on alcohol intake persisted when oxycodone was removed. Additionally, re-exposure to oxycodone cues in combination with the administration of the pharmacological stressor yohimbine drove reinstatement of oxycodone seeking in females but did not have a strong effect in males, possibly due to low levels of oxycodone intake during active self-administration in male rats. Additionally, yohimbine drove increased alcohol consumption, in line with prior findings from our group and others. CONCLUSIONS: Taken together, this study demonstrates that rats will concurrently self-administer both oxycodone and alcohol in operant chambers, and this procedure can serve as a platform for future investigations in polysubstance use and relapse-like behavior.