Effects of repeated social defeat on adolescent mice on cocaine‐induced CPP and self‐administration in adulthood: integrity of the blood–brain barrier

Abstract

Social stress in adulthood enhances cocaine self-administration, an effect that has been related with an increase in extracellular signal-regulated kinase and p38α mitogen-activated protein kinase phosphorylation. A detrimental effect of cocaine on blood-brain barrier (BBB) integrity has also been reported. This study evaluates the effects of repeated social defeat (RSD) during adolescence on the reinforcing and motivational effects of cocaine in adult mice and the changes induced by RSD on BBB permeability. Cocaine self-administration, conditioned place preference and quantitative analysis of claudin-5, laminin, collagen-IV and IgG immunoreactivity took place 3 weeks after RSD. Mice socially defeated during adolescence developed conditioned place preference and exhibited reinstated preference with a non-effective dose of cocaine (1 mg/kg). RSD mice needed significantly more sessions than control animals for the preference induced by 25 mg/kg of cocaine to be extinguished. However, acquisition of cocaine self-administration (0.5 mg/kg per injection) was delayed in the RSD group. Mice exposed to RSD displayed significant changes in BBB structure in adulthood, with a marked reduction in expression of the tight junction protein claudin-5 and an increase in basal laminin degradation (reflected by a decrease in laminin and collagen-IV expression) in the nucleus accumbens and hippocampus. The detrimental effect induced by cocaine (25 mg/kg) on collagen-IV expression in the hippocampus was more pronounced in RSD mice. In summary, our findings suggest that stress and cocaine can increase the long-term vulnerability of the brain to subsequent environmental insults as a consequence of a sustained disruption of the BBB.

Maternal Separation Impairs Cocaine-Induced Behavioural Sensitization in Adolescent Mice

“…Therefore, a decrease in amphetamine or morphine rewarding effects was reported in rodents exposed to chronic mild stress [31,32], and a neonatal model of stress produced a decrease in the rewarding effects of cocaine evaluated in the CPP [33]. However, enhanced rewarding effects of cocaine were also found in adolescent mice exposed to stress by social defeat [19]. The discrepancy in these previous results may be due to the characteristics of stressful situations in terms of the frequency and duration of stress as well as the age at which the stress situation took place.…”

“…In fact, some behavioural studies have suggested that adolescents are hyposensitivity to psychostimulants effects relative to adult rats [34,35]. Accordingly, in a recent study evaluating the rewarding effects of cocaine in the conditioned place preference, an effective dose of 25 mg/kg of cocaine revealed a significant effect in adolescent OF1 mice [19]. Conversely, the higher dose used in the present study was 15 mg/kg and only a marginally effect was observed in the CPP.…”

“…In this sense, previous studies evaluating the influence of repeated stress have also shown controversial data. Hence, whereas adult social defeat stress resulted in enhanced cocaine self-administration in socially stressed adult mice [39], no differences were found in socially stressed adolescent mice [19]. Therefore, the lack of robust results here reported regarding the rewarding and reinforcing effects of cocaine in the CPP and self-administration paradigm respectively may be also attributed to the fact that we used adolescent mice, showing an important behavioural variability, probably due to brain immaturity [35].…”

“…Experimental studies also showed that cocaine use induces neuroadaptive changes in cellular and synaptic functions, including alterations in the DA system [17]. Several studies have tried to elucidate the link between emotional disorders and substance use disorder, but few reports have evaluated the effects of chronic stress and drugs of abuse during adolescence in rodents [18,19]. Hence, in this study, we investigated the influence of maternal separation on cocaine-induced behavioural effects, including locomotor sensitization and reward in adolescent mice.…”

Enhanced dopamine D2 autoreceptor function in the adult prefrontal cortex contributes to dopamine hypoactivity following adolescent social stress

“…For example, insufficient mPFC dopamine activity during reward processing is associated with both increased impulsive choice (Yates et al, 2014) and perseveration in conditioned response despite changes in reward contingency (Floresco, 2013). In accordance with this, rats defeated in adolescence show enhanced preference for psychostimulantassociated cues even when the drug is no longer available (Burke et al, 2011;Rodriguez-Arias et al, 2017), along with greater alcohol and cocaine self-administration (Burke & Miczek, 2015;Rodriguez-Arias et al, 2017;Rodríguez-Arias et al, 2017). Findings from the current and previous studies suggest that targeting D2 autoreceptors along with DAT to restore dopamine availability in the mPFC could lead to more efficacious treatment of the cognitive deficits seen in adult neuropsychiatric disorders promoted by periadolescent stress (Watt et al, 2017).…”