Cocaine-seeking behaviour is differentially expressed in male and female mice exposed to maternal separation and is associated with alterations in AMPA receptors subunits in the medial prefrontal cortex

According with clinical data, women evolve differently from drug use to drug abuse. Among drugs of abuse, cocaine is the most consumed psychostimulant. Animal studies demonstrated that females show increased motivation to seek cocaine during the self-administration paradigm (SA) than males. Moreover, suffering childhood adversity or major depressive disorder are two factors that could increase the predisposition to suffer cocaine addiction. Maternal separation with early weaning (MSEW) is an animal model that allows examining the impact of early-life stress on cocaine abuse. In this study, we aimed to explore changes in MSEW-induced cocaine-seeking motivation to determine potential associations between despair-like behaviour and cocaine-seeking. We also evaluated possible alterations in the AMPA receptors (AMPArs) composition in the medial prefrontal cortex (mPFC) of these mice. We exposed mice to MSEW and the behavioural tests were performed during adulthood. Moreover, GluA1, GluA2 mRNA and protein expression were evaluated in the mPFC. Results show higher cocaine-seeking in standard nest females, as well as an increase in GluA1 and GluA2 protein expression. Moreover, MSEW induces downregulation of Gria2 and increases the Gria1/Gria2 ratio, only in male mice. In conclusion, female mice show different composition of the AMPA receptor in the mPFC and MSEW alters the glutamatergic system in the mPFC of male mice.This study was supported by the Ministerio de Economia y Competitividad (grant number SAF2016-75966-R-FEDER; PID2019-104077-RB-100), Ministerio de Sanidad (Retic-ISCIII, RD16/017/010 and Plan Nacional sobre Drogas 2018/007) to O·V., and the Consejo Nacional de Ciencia y Tecnología in Mexico (CONACYT) (CB-2015-255317 to A.C.-M., 582196 for L.M.-M. and 276577 for A.C-Z). The Department of Experimental and Health Sciences (UPF) is an “Unidad de Excelencia María de Maeztu” funded by the MINECO (Ref. CEXS-2018-000792)