Persistent increase of accumbens cocaine ensemble excitability induced by IRK downregulation after withdrawal mediates the incubation of cocaine craving.

The incubation phenomenon, cue-induced drug craving progressively increasing over prolonged withdrawal, accounts for persistent relapse, leading to a dilemma in the treatment of cocaine addiction. The role of neuronal ensembles activated by initial cocaine experience in the incubation phenomenon was unclear. In this study, with cocaine self-administration (SA) models, we found that neuronal ensembles in the nucleus accumbens shell (NAcSh) showed increasing activation induced by cue-induced drug-seeking after 30-day withdrawal. Inhibition or activation of NAcSh cocaine-ensembles suppressed or promoted craving for cocaine, demonstrating a critical role of NAcSh cocaine-ensembles in incubation for cocaine craving. NAcSh cocaine-ensembles showed a specific increase of membrane excitability and a decrease of inward rectifying channels Kir2.1 currents after 30-day withdrawal. Overexpression of Kir2.1 in NAcSh cocaine-ensembles restored neuronal membrane excitability and suppressed cue-induced drug-seeking after 30-day withdrawal. Expression of dominant-negative Kir2.1 in NAcSh cocaine-ensembles enhanced neuronal membrane excitability and accelerated incubation of cocaine craving. Our results provide a cellular mechanism that the downregulation of Kir2.1 functions in NAcSh cocaine-ensembles induced by prolonged withdrawal mediates the enhancement of ensemble membrane excitability, leading to incubation of cocaine craving.

Accumulation of NMDA receptors in accumbal neuronal ensembles mediates increased conditioned place preference for cocaine after prolonged withdrawal.

Cue-induced cocaine craving gradually intensifies following abstinence, a phenomenon known as the incubation of drug craving. Neuronal ensembles activated by initial cocaine use, are critically involved in this process. However, the mechanisms by which neuronal changes occurring in the ensembles after withdrawal contribute to incubation remain largely unknown. Here we labeled neuronal ensembles in the shell of nucleus accumbens (NAcSh) activated by cocaine conditioned place preference (CPP) training. NAcSh ensembles showed an increasing activity induced by CPP test after 21-day withdrawal. Inhibiting synaptic transmission of NAcSh ensembles suppressed the preference for cocaine paired-side after 21-day withdrawal, demonstrating a critical role of NAcSh ensembles in increased preference for cocaine. The density of dendritic spines in dopamine D1 receptor expressing ensembles was increased after 21-day withdrawal. Moreover, the expression of Grin1, a subunit of the N-methyl-D-aspartate (NMDA) receptor, specifically increased in the NAcSh ensembles after cocaine withdrawal in both CPP and self-administration (SA) mouse models. Targeted knockdown or dysfunction of Grin1 in NAcSh ensembles significantly suppressed craving for cocaine. Our results suggest that the accumulation of NMDA receptors in NAcSh ensembles mediates increased craving for cocaine after prolonged withdrawal, thereby providing potential molecular targets for treatment of drug addiction.

Sex-dependent and long-lasting effects of bisphenol AF exposure on emotional behaviors in mice.

We recently reported that maternal exposure to bisphenol AF (BPAF), an environmental endocrine disruptor (EED), induced significant alterations in emotional behaviors in offspring mice during adolescence in a sex-dependent manner. However, the effects of adult BPAF exposure and the potential long-lasting effects of maternal exposure to BPAF on offspring mice are still unknown. The present study aimed to investigate the neurobehavioral effects of adult and maternal exposure to BPAF, intragastrically (0.4, 4 mg•kg-1, i.g.), by using a series of classic emotional behavioral tests, mainly referring to depression, anxiety, and memory. The results showed that adult BPAF exposure significantly attenuated anxiety- and depression-like behaviors in adult male mice, while increasing anxiety-like behaviors, promoting novel object recognition memory formation, and impairing contextual fear conditioning memory formation in adult female mice. Maternal exposure to BPAF induced anxiety-like effects and anti-depression-like effects in male offspring mice during adulthood, while maternal BPAF exposure increased anxiety- and depression-like behaviors in female offspring mice during adulthood. Our present findings indicate that BPAF exposure significantly affects emotional behaviors in adult/offspring mice in a sex-dependent manner and that female adult mice are more likely to have adverse consequences to BPAF exposure during adulthood, even during early life stages.

Effects of maternal exposure to bisphenol AF on emotional behaviors in adolescent mice offspring.

Exposure to bisphenol A (BPA), one kind of environmental endocrine disruptors (EEDs), exerted significantly detrimental effects on neuro-endocrinological system and related disorders, such as memory dysfunction and depression. Bisphenol AF (BPAF),a newly introduced chemical structurally related to BPA, is used extensively. BPAF has stronger estrogenic activities than BPA. However, the potential neurotoxicological effects of BPAF are still elusive. The present study aimed to investigate the potential effects of maternal BPAF exposure during pregnancy on emotional behaviors of adolescent mice offspring. In male adolescent offspring, maternal exposure to BPAF (0.4, 4.0 mg kg-1, intragastrically administration) induced significant anxiety- and depressive-like behaviors, assessed by open field test (OFT), novelty-suppressed feeding test (NSF), sucrose preference test (SPT), tail suspension test (TST) and forced swimming test (FST). In female adolescent offspring, BPAF exposure at 0.4 mg kg-1 dose reduced the latency to feeding in the NSF test, while increased the floating time in the FST. Maternal BPAF exposure decreased the recognition index in the long term memory (LTM) test in both sexes, while only decreased the freezing time of male offspring in the contextual fear conditioning (CFC) task. These results indicate that maternal exposure to BPAF significantly affect emotion-related behaviors in adolescent mice offspring, and the male offspring with a higher probability to develop symptoms of anxiety and depression and to suffer memory impairment after maternal exposure to BPAF.