Stress changes amphetamine response, D2 receptor expression and epigenetic regulation in low-anxiety rats

The aim of this study was to assess the influence of chronic restraint stress on amphetamine (AMPH)-related appetitive 50-kHz ultrasonic vocalisations (USVs) in rats differing in freezing duration in a contextual fear test (CFT), i.e. HR (high-anxiety responsive) and LR (low-anxiety responsive) rats. The LR and the HR rats, previously exposed to an AMPH binge experience, differed in sensitivity to AMPH's rewarding effects, measured as appetitive vocalisations. Moreover, chronic restraint stress attenuated AMPH-related appetitive vocalisations in the LR rats but had no influence on the HR rats' behaviour. To specify, the restraint LR rats vocalised appetitively less in the AMPH-associated context and after an AMPH challenge than the control LR rats. This phenomenon was associated with a decrease in the mRNA level for D2 dopamine receptor in the amygdala and its protein expression in the basal amygdala (BA) and opposite changes in the nucleus accumbens (NAc) - an increase in the mRNA level for D2 dopamine receptor and its protein expression in the NAc shell, compared to control conditions. Moreover, we observed that chronic restraint stress influenced epigenetic regulation in the LR and the HR rats differently. The contrasting changes were observed in the dentate gyrus (DG) of the hippocampus - the LR rats presented a decrease, but the HR rats showed an increase in H3K9 trimethylation. The restraint LR rats also showed higher miR-494 and miR-34c levels in the NAc than the control LR group. Our study provides behavioural and biochemical data concerning the role of differences in fear-conditioned response in stress vulnerability and AMPH-associated appetitive behaviour. The LR rats were less sensitive to the rewarding effects of AMPH when previously exposed to chronic stress that was accompanied by changes in D2 dopamine receptor expression and epigenetic regulation in mesolimbic areas.