LAUSR

Abstract The effects of alcohol are multifaceted, involving brain circuits regulating reward, motivation, and stress, frequently via the endogenous opioid, beta-endorphin (β-E). It is currently unknown how alcohol affects neural circuit activation in females and how β-E affects ethanol's ability to induce neuronal activation. Therefore, we investigated the impact of acute alcohol treatment on neuronal activation in reward- and stress-related brain circuitry in a sex- and β-E dependent manner. In this study, male and female control (C57BL/6J; β-E+/+) and β-E null (−/−) mice were injected intraperitoneally with 2 g/kg ethanol (EtOH) or saline. Post-injection, animals were sacrificed using ketamine/xylazine and perfused with saline followed by 4% paraformaldehyde. Brain sections (35 μm) were immunohistochemically processed for tyrosine hydroxylase (TH), dopamine's rate-limiting enzyme, and c-fos, a neuronal activation marker. The number of c-fos immunoreactive cell nuclei, TH-immunoreactivity, and TH/c-fos-ir cells were quantified in the nucleus accumbens (NAc), ventral tegmental area (VTA), paraventricular nucleus (PVN), central nucleus of the amygdala (CeA), paraventricular thalamic nucleus (PVA) and Edinger-Westphal nucleus (EW). In females, EtOH increased c-fos expression in the CeA, PVN, EW and NAc shell, while c-fos expression in the VTA, and TH expression in the VTA and NAc, depended on a genotype and treatment interaction. In males, EtOH increased c-fos in the CeA and PVN. EtOH also increased the number of double-labeled cells in the Arc, but only in females. These results suggest that the neurons in females are inherently more sensitive to EtOH, emphasizing the importance of studying the relationship between sex and alcohol addiction.