Effects of Early Life Adversity on Opioid Addiction Vulnerability

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Project Summary Over the past twenty years, the United States has experienced a growing epidemic of opioid use disorder accompanied by high rates of opioid-related mortality. Effective strategies to combat this crisis are urgently needed, and identifying at-risk individuals before they become addicted will be critical for fighting this growing epidemic. Although genetics play a role in addiction vulnerability, they alone cannot account for the dramatic rise in opioid addiction incidence in recent years. Therefore, successful prevention strategies must also consider environmental risk factors. For example, in humans, early-life adversity (ELA), such as low socioeconomic status, trauma, or chaotic environment, is associated with life-long affective problems that indicate dysfunction of the brain’s reward circuitry, including risk-taking behaviors and drug use. However, the neurobiological mechanisms by which this occurs are unknown. My project will examine effects of ELA on drug-seeking behavior and reward circuit function in rats, in pursuit of a mechanistic understanding that will inform novel translational intervention or prevention strategies for opioid addiction. To this end, I will implement a powerful, naturalistic model of ELA in rats. In this model, poverty is simulated by providing limited bedding and nesting materials to a postpartum dam. This provokes chaotic patterns of maternal care that are analogous to humans experiencing ELA, and the resulting chronic stress induces profound changes in reward circuits. To understand the behavioral implications of these disrupted circuits, I will use established methods for modeling opioid addiction including self- administration, extinction resistance, and reinstatement, as well as a recently-developed, translationally-relevant behavioral economic model of opioid seeking that can also be used to quantify addiction severity in humans. Building upon my recently-published findings that ELA-reared female rats are remarkably vulnerable to developing opioid addiction-like behaviors, I will determine how ELA interacts with biologic sex to alter vulnerability to opioid addiction in a potentially sex-specific manner. To define the neurobiological mechanisms that underlie ELA-induced opioid vulnerability, I will test whether ELA alters heroin-induced activity within the nucleus accumbens (NAc), and whether restoring normal activity in this region reverses augmented opioid- seeking, thereby identifying a causal mechanism by which ELA shapes reward circuity to increase opioid addiction vulnerability. These studies represent a unique opportunity to understand the role of developmental risk factors in opioid addiction and will elucidate the neurobiological mechanisms that underlie these vulnerabilities.