Maternal separation affects expression of stress response genes and increases vulnerability to ethanol consumption.

Introduction: Maternal separation is an early life stress event associated with behavioral alterations and ethanol consumption. We aimed to expand the current understanding on the molecular mechanisms mediating the impact of postnatal stress on ethanol consumption.

Methods: In the first experiment (T1), some of the pups were separated from their mothers for 6 hr daily (Maternal Separation group - MS), whereas the other pups remained in the cage with their respective mothers (Control group - C). In the second experiment (T2), mice from both groups were subjected to the model of free-choice between water and sucrose solution or between water and ethanol solution. Maternal behavior was assessed at the end of T1. At the end of both T1 and T2, pups were subjected to the light/dark box behavioral test and blood corticosterone concentrations were analyzed.

Results: Our maternal separation protocol led to intense maternal care and affected weight gain of the animals. The expression of stress response genes was altered with higher levels of Crh and Pomc being observed in the hypothalamus, and higher levels of Crhr1 , Crhr2 , Htr2a and lower levels of Nr3c1 and Htr1a being observed in the hippocampus after T1. At the end of T2, we observed higher levels of Avp and Pomc in the hypothalamus, and higher levels of Crhr1 , Crhr2 , Nr3c1 , Slc6a4, Bdnf and lower levels of Htr1a in the hippocampus. Additionally, maternal separation increased vulnerability to ethanol consumption during adolescence and induced changes in anxiety/stress-related behavior after T2. Furthermore, voluntary ethanol consumption attenuated stress response and modified expression of reward system genes: enhancing Drd1 and Drd2 , and reducing Gabbr2 in the striatum.

Conclusion: Maternal separation induced behavioral changes and alterations in the expression of key genes involved in HPA axis and in the serotonergic and reward systems that are likely to increase vulnerability to ethanol consumption in adolescence. We demonstrated, for the first time, that ethanol consumption masked stress response by reducing the activity of the HPA axis and the serotonergic system, therefore, suggesting that adolescent mice from the MS group probably consumed ethanol for stress relieving purposes.