Unraveling the molecular mechanisms involved in alcohol intake and withdrawal in adolescent mice exposed to alcohol during early life stages

Alcohol interferes with foetal development and prenatal alcohol exposure can lead to adverse effects known as foetal alcohol spectrum disorders. We aimed to assess the underlying neurobiological mechanisms involved in alcohol intake and withdrawal in adolescent mice exposed to alcohol during early life stages, in discrete brain areas. Pregnant C57BL/6 female mice were exposed to binge alcohol drinking from gestation to weaning. Subsequently, alcohol seeking and taking behaviour were evaluated in male adolescent offspring, as assessed in the two-bottle choice and oral self-administration paradigms. Brain area samples were analysed to quantify AMPAR subunits GluR1/2 and pCREB/CREB expression following alcohol self-administration. We measured the expression of mu and kappa opioid receptors both during acute alcohol withdrawal (assessing anxiety alterations by the EPM test) and following reinstatement in the two-bottle choice paradigm. In addition, alcohol metabolism was analysed by measuring blood alcohol concentrations under an acute dose of 3 g/kg alcohol. Our findings demonstrate that developmental alcohol exposure enhances alcohol intake during adolescence, which is associated with a decrease in the pCREB/CREB ratio in the hippocampus, prefrontal cortex and striatum, while the GluR1/GluR2 ratio showed a decrease in the hippocampus. Moreover, PLAE mice showed behavioural alterations, such as increased anxiety-like responses during acute alcohol withdrawal, and higher BAC levels. No significant changes were identified for mu and kappa opioid receptors mRNA expression. The current study highlights that early alcohol exposed mice increased alcohol consumption during late adolescence. Furthermore, a diminished CREB signalling and glutamatergic neuroplasticity are proposed as underpinning neurobiological mechanisms involved in the sensitivity to alcohol reinforcing properties. This work was supported by the Ministerio de Economía y Competitividad (SAF2016-75966-R-FEDER and SAF-2017-85679-R-FEDER), and the Ministerio de Sanidad, Consumo y Bienestar Social (Plan Nacional sobre Drogas 2018/007, Retic-ISCIII-RD16/0017/0010 and Retic-ISCIII-RD16/0017/0007). SM-R received a postdoctoral fellowship from the Conselleria d'Educació, Investigació, Cultura i Esport (APOSTD/2017/102), Generalitat Valenciana, Spain. LC received an FPI grant (BES-2014-070657) from the Ministerio de Economía y Competitividad, Spain. The Department of Experimental and Health Sciences (UPF) is a “Unidad de Excelencia María de Maeztu” funded by the AEI (CEX2018-000792-M). The authors thank Gerald-Patrick Fannon for his English proofreading and editing of the manuscript. The authors declare no conflicts of interest.