Delineating the mechanisms underlying addiction vulnerability using multigenerational rodent models

Abstract

In light of the current opioid epidemic, the past 20 years have made it clear that parental life experiences can significantly impact the behavior and neurobiology of their offspring. Preclinical studies indicate that addiction reflects the interaction of an individual’s environment, genetics, and epigenetic modifications they inherit from their parents. Epigenetic mechanisms - including DNA methylation, histone modification, and small non-coding RNAs – refer to the complex interaction between genes and the environment, which produce heritable changes in germ cells that are transmitted to offspring to ultimately influence the brain development and subsequent vulnerability to develop a substance use disorder. The overarching goal of this dissertation was to characterize the behavioral and neurobiological effects of paternal morphine exposure on addiction-related endpoints in offspring. A highly translational rodent model of paternal morphine self-administration was used to produce first-generation (F1) male and female adolescent and adult offspring. As a reference, offspring derived from morphine-exposed fathers were called morphine-sired offspring, and offspring from saline-exposed fathers were called saline-sired offspring. In chapter 2, we revealed that male morphine-sired progeny are more sensitive over time to the pain-relieving effects of morphine. In the periaqueductal grey, an important pain-related brain region, we identified gene expression changes in regulators of G-protein signaling proteins that could partly account for this phenotype. In chapter 3, we demonstrated that adult morphine-sired male offspring self-administered more morphine; were more motived to earn morphine infusions compared to controls; and had more baseline mu-opioid receptor binding in the ventral tegmental area. Next, in chapter 4, we found that a drug-abstinence period of 90 consecutive days following 60 days of morphine exposure in sires was sufficient to prevent morphine-sired males from self-administering more morphine than controls. In chapter 5, we showed that this addiction-like phenotype did not extend to adolescent male or female offspring. Lastly, in chapter 6, using the incubation of craving paradigm, we found that paternal morphine exposure significantly reduced cue-induced active lever pressing for heroin in morphine-sired males. Taken together, these results add to the growing body of literature that show paternal preconception experiences can impact behavioral and neurobiological endpoints in offspring, perhaps via a(n) epigenetically inherited mechanism(s) in the germline.