Cocaine-Induced Impulsivity is Differentially Expressed in Male and Female Mice Exposed to Maternal Separation and is Associated with Alterations in AMPA Receptors Subunits

Abstract

Impulsivity is a key trait in the diagnosis of major depressive disorder (MDD) and substance use disorder (SUD). MDD is a chronic illness characterized by sadness, insomnia, and loss of interest. SUD is a chronic and relapsing disorder characterized by the consumption of drugs despite their negative consequences. Among drugs of abuse, cocaine is the most consumed psychostimulant. Animal studies demonstrated that increased impulsivity predicts predisposition to acquire cocaine self-administration (SA) behaviour with an increased cocaine-intake. Moreover, early-life stress represents a vulnerability factor to develop depressive disorders and drug 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 impulsivity to determine potential associations between depression-like and cocaine-seeking behaviours in male and female mice. We also evaluated possible alterations in the AMPA receptors (AMPArs) composition and glutamatergic neurotransmission. We exposed mice to MSEW and the behavioural tests were performed during adulthood. Moreover, GluA1, GluA2 mRNA and protein expression were evaluated in the medial Prefrontal Cortex (mPFC). Results showed higher impulsive cocaine-seeking in females, independently the MSEW, as well as an increase in GluA1 and GluA2 protein expression. Moreover, MSEW induced downregulation of Gria2 and increased the GluA1/GluA2 ratio, only in male mice. In conclusion, female mice expressed higher mPFC glutamatergic function, which potentiated their impulsivity during cocaine SA. Also, data indicated that MSEW alters glutamatergic function in mPFC of male mice, increasing the glutamatergic excitability.