BackgroundAdolescent stress and alcohol exposure increase the risk of maladaptive behaviors and mental disorders in adulthood, with distinct sex-specific differences. Understanding the mechanisms underlying these early events is crucial for developing targeted prevention and treatment strategies.MethodsMale and female Wistar rats were exposed to acute restraint stress and intermittent alcohol during adolescence. We assessed lasting effects on plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, and mRNA expression of genes related to corticotropin releasing hormone (CRH), neuropeptide Y (NPY), corticoid, opioid, and arginine vasopressin systems in the amygdala and hypothalamus.ResultsThe main findings are as follows: (1) blood alcohol concentrations (BAC) increased after the final alcohol administration, but stressed males had lower BAC than non-stressed males; (2) Males gained significantly more weight than females; (3) Stressed females showed higher ACTH levels than non-stressed females, with no changes in males; (4) Stress increased CORT levels in males, while stressed, alcohol-treated females had lower CORT levels than non-stressed females; (5) CRH: Females had lower Crhr1 levels in the amygdala, while alcohol reduced Crhr2 levels in males but not females. Significant interactions among sex, stress, and alcohol were found in the hypothalamus, with distinct patterns between sexes; (6) NPY: In the amygdala, stress reduced Npy and Npy1r levels in males but increased them in females. Alcohol decreased Npy2r levels in males, with varied effects in females. Similar sex-specific patterns were observed in the hypothalamus; (7) Corticoid system: Stress and alcohol had complex, sex-dependent effects on Pomc, Nr3c1, and Nr3c2 in both brain regions; (8) Opioid receptors: Stress and alcohol blunted the elevated expression of Oprm1, Oprd1, and Oprk1 in the amygdala of males and the hypothalamus of females; (8) Vasopressin: Stress and alcohol interacted significantly to affect Avp and Avpr1a expression in the amygdala, with stronger effects in females. In the hypothalamus, alcohol increased Avp levels in females.ConclusionsThis study demonstrates that adolescent acute stress and alcohol exposure induce lasting, sex-specific alterations in systems involved in reward and stress responses. These findings emphasize the importance of considering sex differences in the prevention and management of HPA dysfunction and psychiatric disorders. Experiencing stress and consuming alcohol during the teenage years can significantly raise the risk of developing mental health problems later in life. These risks can vary between males and females, making it important to understand how each sex is differently affected. This study investigated how exposure to acute stress and intermittent alcohol use during adolescence impacts male and female rats as they reach young adulthood. Our research involved first measuring the levels of stress hormones in the blood to see how these early experiences influenced the body's stress response. Following this, we closely examined changes in the expression of specific genes within two critical brain regions: the amygdala and the hypothalamus. These regions play a crucial role in controlling emotional states, managing stress, and regulating behaviors related to addiction. The results of the study revealed that both stress and alcohol exposure during adolescence led to lasting alterations in stress hormone levels and changes in the expression of genes within the brain. Importantly, these effects were not the same for males and females, highlighting the presence of sex-specific differences. Understanding these differences can guide the development of more effective treatments, ultimately improving mental health outcomes for both males and females. Acute stress led to decreased BAC levels in male rats after the final alcohol administration in a binge drinking model, without effects on female rats.Stressed female rats showed elevated ACTH levels compared to non-stressed females, while interactions between stress and alcohol produced sex-specific effects on CORT levels.Adolescent alcohol increased Crh gene expression in the amygdala in both sexes, with additional sex-dependent alterations in related receptor genes in the amygdala and hypothalamus.Stress and alcohol had sexually dimorphic effects on Npy gene expression in the amygdala, lowering levels in stressed males but increasing them in stressed females.The expression of opioid receptor genes, such as Oprm1 and Oprd1, was significantly altered by adolescent stress and alcohol exposure, with sex-specific patterns in the amygdala and hypothalamus.
