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Abstract
A major DSM-5 criterion for AUD is the continuation of 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 ethanol despite this adulteration are said to be aversion resistant. Studies in our lab have indicated a sex difference in compulsive alcohol drinking in which males suppress their drinking more strongly after the addition of quinine compared to females. This suggests that females are more resistant to quinine-induced suppression of alcohol intake. Fos immunohistochemistry revealed sex differences in neuronal activation patterns in three brain regions during quinine-adulterated alcohol drinking: the ventromedial prefrontal cortex (vmPFC), posterior insular cortex (PIC), and ventral tegmental area (VTA). Specifically, males displayed increased activation in vmPFC and PIC, while females showed increased Fos activation in the VTA.To delve deeper into these sex differences, we examined the specific types of neurons activated in these regions. We once again identified that females were more aversion-resistant compared to males. RNAscope in situ hybridization revealed higher colocalization of glutamate and Fos in vmPFC and PIC in males, while females displayed greater dopamine and Fos colocalization in the VTA. These findings suggest that glutamatergic output from vmPFC and PIC suppresses aversion-resistant alcohol consumption, while dopamine activity in the VTA promotes it.
Expanding our focus to hormonal influences, ovariectomies were conducted to assess the role of circulating ovarian hormones in aversion-resistant alcohol intake and neuronal activation patterns. Ovariectomy reduced quinine-adulterated alcohol intake, indicating that ovarian hormones play a role in aversion-resistant intake, and estradiol supplementation reversed this effect. Additionally, reduced neuronal activation in the VTA of ovariectomized mice was observed. Because we have not observed behavioral effects of hormonal variation during the estrous cycle, our data suggests that a threshold level of circulating estradiol contributes to aversion-resistant alcohol intake and VTA neuronal activity, and that this is not influenced by changes across the cycle.
Our comprehensive study unveils sex-specific differences in aversion-resistant alcohol intake and associated neuronal activation patterns, shedding light on the intricate interplay of sex hormones and neurocircuitry in aversive drinking behaviors.