Stress can trigger pathological changes in behavior and appears to augment substance abuse vulnerability. Nonetheless, only a portion of individuals who experience similar stress events develop any appreciable pathology, thus individuals may express either a susceptible or resilient phenotype following stress. Recent evidence suggests that susceptibility and resilience following stress are associated with distinct adaptations to the mesolimbic dopamine system, which is well known to participate in the development of substance use disorder. Whether increased substance use vulnerability selectively corresponds with the unique behaviors and physiology associated with susceptibility and resilience remains unknown. For our preliminary studies we exposed rats to predator scent stress, and segregated subjects as susceptible or resilient based on the context avoidance and heightened anxiety behavior in the elevated plus maze. Using this approach, we found that susceptibles but not resilients, display an increased propensity to self-administer cocaine. Further, we have identified that distinct dopamine system changes are associated with the susceptible phenotype. In combination with our preliminary studies, the proposed studies are designed to first determine the net effect of terminal and somatodendritic DA system alterations using in vivo measurements of DA activity, and second to isolate the sources of net changes in DA signaling by examining DA terminals or DA neuron soma independently.
Divergent changes in dopamine system function determine susceptibility versus resilience following stress, and it is well accepted that changes in the dopamine system are important in the development of cocaine use disorder. We will use a combination of behavioral, neurochemical, and electrophysiological approaches to determine how different changes in dopamine systems influence the propensity to develop cocaine use disorder. Successful completion of the proposed work will elucidate biological disruptions that predispose individuals with stress-associated psychiatric disorders to developing substance use disorders, and may unveil potential targets for therapeutic treatment.
| Brodnik, Zachary D; Black, Emily M; Clark, Meagan J et al. (2017) Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine. Neuropharmacology 125:295-307 |
