The impact of maternal separation stress on the CRFergic system in the extended amygdala and its relevance to acute stress-induced ethanol consumption in mice.

Maternal separation (MS) is an early-life stressor associated with increased vulnerability to alcohol use disorders (AUD) later in life, potentially through alterations in corticotropin-releasing factor (CRF) signaling in the extended amygdala-comprising the bed nucleus of the stria terminalis (BNST) and amygdala (AMY). This study investigated the long-term effects of MS on ethanol consumption and CRFergic signaling following acute stress, considering possible sex-dependent differences. C57BL/6J pups were subjected to the MS paradigm from postnatal days (PND) 1-14; controls remained undisturbed. On PND 45, mice underwent an Drinking in the Dark (DID) protocol for three weeks, followed by operant alcohol self-administration under a fixed ratio schedule. They were then tested under a progressive ratio (PR) reinforcement schedule. After PR, a subset of mice was randomly assigned to the Rat Exposure Test (RET), while a second subset of mice was kept naïve for it. Finally, a 4h-binge session was allowed for all the animals. Results showed that female groups, independent of MS stress, consumed more ethanol than male groups during DID. Male MS mice spent more time in the home chamber during RET, which was associated with increased number of reinforcements and active nose pokes during binge protocol. MS mice not exposed to RET showed increased CRF-binding protein in the AMY and reduced CRFR1 receptor in the BNST; RET exposure led to increased CRFR2 receptor expression in the AMY of MS mice. These findings suggest that MS alters alcohol consumption, particularly in response to acute stress, in a sex-dependent manner, and the CRFergic system of mice exposed chronically to this substance.