Effects of adolescent stress on behavioral and neural amphetamine responses in adulthood

Final maturation of mesocorticolimbic dopamine systems occurs during adolescence. Exposure to social stress, such as bullying, during this period of human development results in behavioral dysfunction and is correlated with adult psychiatric and substance abuse disorders. Previous studies established an adolescent social defeat model using male Sprague-Dawley rats to characterize neuroendocrine changes resulting from adolescent bullying that may underlie such alterations in adult behavior. Furthermore, previous studies suggest that adolescent exposure to defeat decreases medial prefrontal cortex dopamine (mPFC) tissue content. Adolescent rats at postnatal (P) day 35 were exposed to a bout of social defeat once per day for five days. Controls were placed in empty novel cages at matched times. Rats were left undisturbed their home cage until early adulthood (P56+). Adolescent defeat attenuated locomotion in response to acute 2.5 mg/kg amphetamine. This was accompanied by blunted amphetamine-induced increase in mPFC dopamine tissue concentrations following adolescent defeat. In the adult nucleus accumbens (NAc) core following adolescent defeat, there was elevated amphetamine-induced increase in dopamine tissue concentrations. Moreover, adult amphetamine-induced increases in corticosterone were blunted following adolescent defeat. Adult locomotion was increased in two different novel environments following adolescent defeat, suggesting vulnerability to amphetamine reinforcement. In a separate experiment, adolescent defeat increased adult place preference for 1.0 mg/kg amphetamine-paired cues. In contrast, experience with non-social stress during adolescence did not increase amphetamine place preference. Furthermore, the amphetamine-induced reduction of NAc core D2 dopamine receptors during amphetamine conditioning was absent in adults subjected to adolescent defeat. In the final study, adolescent defeat increased locomotion in response to an acute 1.0 mg/kg amphetamine in adulthood, while adolescent defeat did not have an effect on amphetamine-induced locomotion after repeated 1.0 mg/kg amphetamine injections. Furthermore, acute amphetamine-induced mPFC dopamine release was nearly absent following adolescent defeat, while amphetamine-induced mPFC dopamine release was normalized following repeated amphetamine injections. In addition, adult NAc core dopamine release was not altered by adolescent defeat. These results suggest that adolescent defeat increases behavioral responsiveness to low dose amphetamine in early adulthood and implicates reduced mPFC dopamine and altered NAc core D2 receptors as underlying neural mechanisms.