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.

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 cocaineseeking 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.

Brief Maternal Separation Inoculates Against the Effects of Social Stress on Depression-Like Behavior and Cocaine Reward in Mice

“…MSEW causes an impairment of cocaine-induced behavioral sensitization, possibly due to a dysfunction of the dopaminergic system, a potential vulnerability factor for the development of substance use disorders ( Gracia-Rubio et al, 2016 ). In addition, mice exposed to MSEW expressed higher cocaine intake, an enhanced vulnerability to the acquisition of cocaine self-administration, and an incapacity for this behavior to be extinguished ( Castro-Zavala et al, 2020 ; Castro-Zavala et al, 2021a ; Castro-Zavala et al, 2021b ). In the CPP paradigm, MS (3h/day, from PND2 to PND14-15) also increased vulnerability to cocaine reward in adolescent rats ( Alves et al, 2020 ) and mice ( Viola et al, 2016 ), suggesting that this early life stress subsequently enhances the motivational salience of stimuli associated with cocaine.…”

“…No studies have been performed about the inoculating effect of MS on the subsequent response of stressed animals to drugs of abuse. However, studies of the mechanisms than underlie the effects of more stressful protocols of MS on the rewarding properties of cocaine have revealed that MS modifies the activity of AMPA and NMDA receptors in structures of the brain reward circuit and other areas involved in the learning of cocaine-cue association ( Ganguly et al, 2019 ; Castro-Zavala et al, 2020 ; Castro-Zavala et al, 2021b ). MSEW was seen to enhance glutamatergic function in the nucleus accumbens and increase excitability of ventral tegmental area DA neurons ( Castro-Zavala, et al, 2021a ).…”

“…In this sense, maternal separation (MS) stress constitutes a critical experience that can induce behavioural alterations and neuropsychiatric disorders in later life ( George et al, 2010 ; Gracia-Rubio et al, 2016 ; Lukkes et al, 2017 ; Zhou et al, 2020 ). Repeated episodes of MS (4–8 h per day, from postnatal day (PND) two to PND16) have been shown to increase the vulnerability of offspring to the rewarding effects of drugs of abuse during adolescence or adulthood ( Delavari et al, 2016 ; Viola et al, 2016 ; Orso et al, 2017 ; Castro-Zavala et al, 2020 ; Castro-Zavala et al, 2021a; Castro-Zavala et al, 2021b ; Arenas et al, 2022 ). Furthermore, different procedures of repeated MS (for 4–8 h per day, from PND2 until PND12-20) enhance the anxiety of adolescent mice in the elevated plus maze (EPM) ( Shin et al, 2016 ; Wang et al, 2017 ) and in the social preference test ( Wang et al, 2017 ) and induce anhedonia in the saccharin preference test ( Wang et al, 2017 ) and depression-like behaviour in the forced swimming test ( He et al, 2020 ).…”

Adolescent cocaine induced persistent negative affect in female rats exposed to early-life stress

“…In the last years, cumulative evidence has proved biologically based sex differences in all phases of drug addiction (for all drugs in general, but including cocaine; e.g., Becker and Chartoff 2019 ), exhibiting females a more rapid escalation from casual drug taking to addiction, a greater withdrawal response with abstinence (i.e., increased negative affect), and a tendency for a negative treatment outcome (reviewed in Becker and Koob 2016 ). Moreover, while stress exposure early in life is a well-accepted risk factor for modeling mood disorders in rodents, and having a prior psychiatric vulnerability is also a key trigger for drug consumption (e.g., self-treatment to manage negative affect; Levis et al 2021 ), the combination of both risk factors has proven to induce different responses between sexes (e.g., Alves et al 2020 ; Castro-Zavala et al 2020 , 2021 ; Levis et al 2021 ). One of the simplest models to mimic a depressive-like phenotype in rodents by early-life stress applies a single episode (24 h) of maternal deprivation on postnatal day (PND) 9 (Ellenbroek et al 1998 ), since it interferes with their normal brain developmental trajectories and modifies their behavioral and neurochemical outcomes (reviewed in Marco et al 2015 ; also see our results in García-Cabrerizo et al 2020 ; Bis-Humbert et al 2021a ).…”

Bmal1-knockout mice exhibit reduced cocaine-seeking behaviour and cognitive impairments

“…The cocaine SA paradigm was conducted as previously described [39][40][41] . Nosepoking into the active hole resulted in a cocaine infusion (0.75 mg/kg/infusion) and nosepoking into the inactive hole had no consequences.…”