The Developmental Origins of Opioid Use Disorder and Its Comorbidities

Abstract

Opioid use disorder (OUD) rarely presents as a unitary psychiatric condition, and the comorbid symptoms likely depend upon the diverse risk factors and mechanisms by which OUD can arise. These factors are heterogeneous and include genetic predisposition, exposure to prescription opioids, and environmental risks. Crucially, one key environmental risk factor for OUD is early life adversity (ELA). OUD and other substance use disorders are widely considered to derive in part from abnormal reward circuit function, which is likely also implicated in comorbid mental illnesses such as depression, bipolar disorder, and schizophrenia. ELA may disrupt reward circuit development and function in a manner predisposing to these disorders. Here, we describe new findings addressing the effects of ELA on reward circuitry that lead to OUD and comorbid disorders, potentially via shared neural mechanisms. We discuss some of these OUD-related problems in both humans and animals. We also highlight the increasingly apparent, crucial contribution of biological sex in mediating the range of ELA-induced disruptions of reward circuitry which may confer risk for the development of OUD and comorbid neuropsychiatric disorders.

Keywords: addiction; anhedonia; circuit; early life stress; extinction; opioids; reward; sex.

Figure 1

Early life adversity (ELA) augments opioid-seeking behaviors and increases the demand for opioid drugs and highly palatable food. Adapted from Figures 1, 2 in Levis et al. (2019). (A) Female LBN-experienced (ELA) rats trained to self-administer intravenous heroin engage in more persistent heroin-seeking behavior after the withdrawal of the drug and (B) augmented relapse induced by heroin-associated cues than their control (CTL) counterparts. (C,D) On an economic task measuring sensitivity to increasing cost to obtain the desired reward, ELA rats are willing to exert more effort to access both opioid drug and food rewards at a higher cost than controls. This indicates increased demand for opioids and highly palatable food that is relatively insensitive to high costs. *p < 0.05; ***p < 0.001.