Low-anxiety rats are more sensitive to amphetamine in comparison to high-anxiety rats

This study utilised the two injection protocol of sensitisation (TIPS) and the conditioned place preference test to validate and extend previous findings on the effects of amphetamine on positive reinforcement-related 50 kHz ultrasonic vocalisation (USV) in rats. We also examined changes in the expression of c-Fos and the NMDA receptor 2B (GluN2B) subunit, markers of neuronal activity and plasticity, in brain regions of rats in response to TIPS. We used low anxiety-responsive (LR) and high anxiety-responsive (HR) rats, which are known to exhibit different fear-conditioned response strengths, different susceptibilities to amphetamine in the TIPS procedure and different amphetamine-dependent 50 kHz USV responses. The LR rats, compared to the HR rats, not only vocalised much more intensely but also spent significantly more time in the amphetamine-paired compartment. After the second dose of amphetamine, the LR rats exhibited more c-Fos and GluN2B activation in layers II and III of the M1/M2 motor cortex area and prefrontal cortex (PRE, PRL, IL) and also presented with more GluN2B activation in the basal amygdala. These data reveal that HR and LR rats exhibit different levels of reactivity in the cortical-limbic pathway, which controls reward-related motivational processes. These findings contribute to the general hypothesis that heterogeneity in emotional processes is one of the causes of sensitisation to amphetamine and drug addiction.