Affective and addictive consequences of adolescent stress in rats selectively bred for differences in emotional reactivity

Aydin C, Frohmader KS, Blandino P, Akil H
Society for Neuroscience. 2016.


In humans, certain temperamental characteristics can predict the propensity for mood disorders and substance abuse. One such personality trait, novelty-seeking behavior, is modeled in rats by identifying outbred rats as high (HR) versus low (LR) responders based on their locomotor reactivity to the mild stress of a novel environment. Compared to LRs, HRs display lower anxiety- and depression-like behaviors and higher vulnerability for drug seeking behavior. To ascertain the genetic and developmental underpinnings of these phenotypes, our laboratory has employed a selective breeding strategy to amplify and segregate these naturally occurring differences generating two lines, the bred HR (bHR) and bred LR (bLRs) rats. We have shown that these lines exhibit stable, predictable and profound differences in multiple facets of affective behavior suggesting a pervasive difference in emotionality. The present study investigated how environmental interventions interact with the genetic differences that bHRs and bLRs exhibit to alter affective and addictive behaviors. We employed a chronic variable stress (CVS) regimen in adolescence, and determined the effects of this manipulation on depression-like behavior, and vulnerability to substance abuse. Our results showed that adolescent CVS exposure resulted in affective resilience in bLRs, but vulnerability in bHRs to a stress challenge in adulthood. This phenotype-switch in affective behavior was accompanied by changes in the mRNA levels of genes associated with neuronal maturation and survival, in the hippocampus. Moreover, a phenotype-switch was also observed in cocaine sensitization in CVS-exposed bLRs and bHRs, in that, CVS-experienced bHRs showed a reduction in sensitization, while bLRs displayed a sensitized response to cocaine. Molecular analyses showed that the CVS-related differences in cocaine sensitization might be mediated by dopaminergic signaling in the nucleus accumbens and the hippocampus. Overall, these findings indicate that the effects of CVS on animals with differential stress reactivity depends highly on the age of stress exposure, and confirm that environmental challenges encountered in adolescence interact with genetic background to alter affective and addictive behaviors later in life. Understanding the neurobiological underpinnings of individual differences in resilience vs vulnerability to affective and addictive behaviors is crucial for developing personalized treatment strategies.!/4071/presentation/29661