The opioid epidemic is an increasing threat to public health, with opioid-involved overdose fatalities surpassing 81,000 in 2022 – a 64% increase from 2019 (National Institute on Drug Abuse, 2024). Initial opioid use often begins with prescription opioids (POs) prior to the development of opioid use disorder (OUD) (Dickson-Gomez et al., 2022, Jones, 2013, Lankenau et al., 2012, Veliz et al., 2022). PO misuse alone accounted for 88.2% of the 8.9 million self-reports of opioid use in people aged 12 or older in 2022 (Substance Abuse and Mental Health Services Administration, 2022). Moreover, an estimated 75% of young individuals who use drugs report initiating opioid use with a PO (Lankenau et al., 2012). Among POs, oxycodone has been ranked by individuals with OUD as the most desirable and “addictive”, and is the most commonly used PO by individuals who primarily use heroin (Remillard et al., 2019, Rosenblum et al., 2007). Consequently, it is imperative to identify factors that may predispose individuals to oxycodone misuse in at-risk populations.

As a critical developmental period, the experience of stress or trauma during adolescence has been associated with increased risk for substance use disorders (SUD) (Dube et al., 2003, Skeer et al., 2009) as well as for mood and/or anxiety disorders (e.g., major depressive disorder, bipolar disorder, generalized anxiety disorder, post-traumatic stress disorder) (Basedow et al., 2020, Benjet et al., 2010, Jaworska-Andryszewska and Rybakowski, 2019, McLaughlin et al., 2012, Scott et al., 2012) that are linked with enhanced vulnerability for substance use and which often present comorbid with SUDs (Calarco and Lobo, 2021, Davis et al., 2017, Langdon et al., 2019, Patton et al., 2024, Preuss et al., 2021). In particular, OUD has been associated with a history of stress during adolescence (Austin and Shanahan, 2018, Conroy et al., 2009, Quinn et al., 2016, Swedo et al., 2020), with some estimates showing populations experiencing adolescent trauma have a 2.7-fold increase in opioid use (Heffernan et al., 2000). Despite these associations in clinical populations, preclinical studies investigating the effect of adolescent stress on opioid reinforcement in animal models are conflicting. For example, social isolation stress during adolescence increased self-administration of inhaled sufentanil (Weinhold et al., 1993) and IV remifentanil (Hofford et al., 2017) in male rats and enhanced IV fentanyl self-administration in male and female rats (Bardo et al., 2023). However, other studies have reported either no effect of early-life/adolescent social isolation stress on initial oral morphine consumption or IV remifentanil self-administration in adult rats (Marks-Kaufman and Lewis, 1984, Thorpe et al., 2020), or attenuated opioid-induced conditioned place preference following adolescent social isolation stress (Schenk et al., 1985, Wongwitdecha and Marsden, 1996). Notably, no studies to date have characterized whether oxycodone reinforcement specifically is affected by adolescent stress, and most prior studies did not include female subjects. Additionally, all aforementioned studies relied on social isolation as a chronic stressor during adolescence, despite clinical reports indicating that the experience of even a single traumatic event is sufficient to increase the risk for post-traumatic stress disorder and/or SUD (Bryant et al., 2012; Degenhardt et al., 2022; Garrey et al., 2023; McCann-Pineo et al., 2021; Solomon et al., 1993; Takemoto et al., 2020; Wilcoxon et al., 2021).

The goal of this study was to examine whether acute adolescent stress impacts IV oxycodone self-administration in male and/or female rats. We employed a single exposure to predator odor during concurrent physical restraint as the stressor, based on previous evidence that presentation of this stressor during adolescence induces an anxiety-like behavioral and neurophysiological phenotype in male rats (Borodovitsyna et al., 2022, Borodovitsyna et al., 2018). We first investigated whether exposure to this stressor during adolescence alters initial acquisition of oxycodone self-administration. We then assessed maintenance of oxycodone self-administration under FR1 and FR3 schedules of reinforcement. Finally, we examined oxycodone reinforcement during progressive-ratio (PR) probe tests. To determine whether any observed stress effects were specific to opioid reinforcement, we also evaluated the effects of adolescent stressor exposure on sucrose-maintained responding in separate animals.