This study used the conditioned place preference test to explore the effects of subchronic amphetamine administration on drug-associated cues in rats with different emotional reactivity. We also examined the changes in markers of dopaminergic activity in brain regions in response to the amphetamine-paired context, after a withdrawal period preceded by subchronic amphetamine treatment. We used low-anxiety (LR) and high-anxiety (HR) rats, which are known to exhibit distinct levels of susceptibility to amphetamine. Compared to HR rats, LR rats spent significantly more time in the amphetamine-paired compartment after the withdrawal period preceded by subchronic amphetamine treatment. Compared to HR control rats, LR control rats showed higher expression of the D1 receptor in the nucleus accumbens core (NAC core) and basolateral amygdala and higher expression of the D2 receptor in the NAC core. After the amphetamine treatment and withdrawal period, the LR rats showed higher D1 receptor expression in the NAC core, an increased level of homovanilic acid (HVA) in the prefrontal cortex, the NAC and the central amygdala than HR rats, as well as lower D2 receptor expression in the NAC core and the amygdala than LR control rats.
These results indicate that the differences in the activity of the dopaminergic mesolimbic system in the HR and LR rats are maintained and even enhanced after a multi-day break in the use of the drug, indicating the occurrence of sensitisation. These findings show that the innate reactivity of the limbic dopaminergic innervations, dependent on the level of emotional reactivity, may significantly and chronically modify the development and maintenance of sensitisation to amphetamine.