People subjected to traumatic experiences are especially susceptible to the abuse of depressants, including opiates and opioids. However, not everyone responds the same way to stress; there is evidence of both individual vulnerability as well as individual resilience to such stresses. Traumatic psychological stress, often accompanied by physical trauma, can include harassment, sexual abuse, bullying, domestic violence, life-threatening events, and other subjective negative experiences. It is known that stress is an important factor in the development of addiction disorders, and it is generally understood what critical neurobiological substrates underlie this mechanism. What is not known is how individual vulnerability or resilience to stress relates to susceptibility to use and abuse opioids and what neurobiological markers may be associated with these individual differences. Furthermore, current preclinical approaches to model heroin use and stress comorbidity are limited in scope and do not closely resemble clinical pathology. We recently started developing a preclinical model of heroin use and stress comorbidity that better parallels clinical development of this phenotype. Based on that work we recently submitted an R01 grant proposal that was designed to assess neural substrates involved in stress and heroin use comorbidity using pharmacological approaches. The reviewers agreed that the scope of the project fits into current need to better understand these processes but expressed some concerns that we are proposing to address in this proposal for CIBBR Pilot Project. The two major concerns center around the idea that increase in economic demand for heroin (a main tool used in our proposal) does not necessarily represent a maker of a “vulnerable to heroin use” phenotype. In addition, our pharmacological approach targeting serotonergic and noradrenergic systems in our preparation does not rely on concrete biomarkers derived from the experimental design we are using in our grant proposal. To address these gaps, we design a study that uses behavioral economics approach to confirm that high economic demand for heroin correlates with already established behavioral markers of substance use phenotype like responding in the face of negative consequences or choice test with an alternative appetitive primary reinforcer. We also embedded in the same study a final phase where we can assess neural substrates involved in heroin-precipitated relapse. Using these elements, the experiments proposed in this study will provide much needed programmatic findings that for the first time will define a constellation of behavioral and neural markers forming a phenotype of rats vulnerable to the heroin use. These findings will serve as an additional preliminary data for the upcoming R01 grant proposal and should significantly strengthen our chances to compete.
