Long maternal separation accelerates behavioural sensitization to ethanol in female, but not in male mice

Early life stress is associated with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, and with aspects involved in drug abuse. In this study, we investigated the effects of brief (BMS) and long maternal separation (LMS) on the HPA axis response and behavioural sensitization to ethanol (EtOH) in male and female mice. From PND 2 to 14, pups were subjected to daily maternal separation for 15 min (BMS) or 180 min (LMS) or no separated, only handled during cage cleaning (animal facility rearing-AFR). As adults, animals were treated every other day with saline (SAL) or EtOH (2.2g/kg), i.p., for 10 days, and immediately after each administration, their locomotor response was evaluated for 15 min. Forty-eight hours after the 5th administration, all animals were challenged with saline, followed 48 h later, by an EtOH challenge. Corticosterone (CORT) plasma levels were determined 3 times: basal, after the 1st administration and after the EtOH challenge. LMS females showed higher CORT levels than BMS females at basal, but not in response to acute or chronic EtOH administration. The CORT response to EtOH was more robust in LMS and BMS male than AFR male mice. Repeated EtOH treatment induced behavioural sensitization in all groups of male mice. In females, LMS induced a faster sensitization, although BMS females also exhibited behavioural sensitization (4th day and 5th day of treatment, respectively). In conclusion, LMS and BMS produced gender-dependent effects. In females, LMS and BMS facilitated the development of behavioural sensitization, but in the LMS group this effect occurred faster, which may represent increased vulnerability to drug abuse. Moreover, LMS females showed higher basal CORT levels compared to BMS. In males, LMS and BMS increased the CORT response to EtOH but did not modify behavioural sensitization. Therefore, we postulate that LMS female mice exhibited a faster development of behavioural sensitization, but CORT levels were not involved with this effect.