Substance-use disorders (SUDs) are characterized by cycles of use, abstinence, and relapse triggered by drug-related stimuli (Saunders 2017; American Psychiatric Association 2022). Environmental contexts and cues associated with drug use can trigger craving and relapse despite long periods of abstinence, a phenomenon known as incubation of craving (Gawin and Kleber, 1986, Ehrman et al., 1992, Foltin et al., 2000). Early drug exposure increases the risk for long-term consequences related to use and the potential to develop SUDs (Ramo and Brown, 2008, Ramo et al., 2012, Winters et al., 2014). Recent studies show that the severity of SUDs during adolescence is linked to continued problems with substance abuse into adulthood (McCabe et al., 2022, Volkow and Wargo, 2022). The pattern of drug use and the types of stimuli that precipitate relapse are unique for adolescents, with up to 86% of those suffering from SUDs returning to drug use within a year (Winters et al., 2014, Silvers et al., 2019). Despite these known risks, little is known about the craving process in adolescents during drug-free periods (Acri et al., 2012, Silvers et al., 2019, Squeglia et al., 2019). An improved understanding of the abstinence period during adolescence, and how it differs from adults, is needed.

Rodent models of cocaine self-administration have provided foundational information about the types of stimuli that elicit relapse and incubation of craving. From adult models, it is clear that cocaine-associated explicit cues, environmental contexts, stress and cocaine promote relapse to cocaine-seeking behavior (Bossert et al., 2013, Feltenstein et al., 2021, Fredriksson et al., 2021). In particular, drug-associated explicit cues are more likely to elicit time-dependent increases in cocaine-seeking behavior, or incubation of craving (Tran-Nguyen et al., 1998, Grimm et al., 2001, Venniro et al., 2021). During adolescence, the associations that are linked with cocaine use have diverse effects on future relapse. In general, adolescent cocaine-exposed rats have similar or reduced cue-induced cocaine-seeking behavior compared to their adult counterparts (Li and Frantz, 2009, Li and Frantz, 2017, Anker and Carroll, 2010, Zbukvic et al., 2016). In contrast, adolescents have heightened stress-induced relapse compared to adults (Anker and Carroll, 2010, Wong and Marinelli, 2016). In regard to cocaine-associated contexts, rats trained in cocaine conditioned place preference (CPP) during adolescence show increased preference for a cocaine-paired context as adults and resistance to extinguish CPP, and mice with a history of oral sucrose-cocaine during adolescence display increased habit-like, context-induced reinstatement when compared to adults (Badanich et al., 2006, Brenhouse and Andersen, 2008, DePoy et al., 2017, Guerin et al., 2021). Using a modified, abbreviated (ABRV) paradigm in which cocaine self-administration (Coc-SA), extinction (EXT) and relapse occurred during adolescence, we found that adolescent and adult rats displayed similar levels of context-induced cocaine-seeking behavior (Cho et al. 2020). Together, these findings suggest that the modality of cocaine-related associations formed during adolescence uniquely impacts relapse later in life.

In regard to incubation of craving, there is evidence that adolescent cocaine-exposed rats show similar or reduced incubation to cocaine-associated cues compared to their adult counterparts and respond at similar magnitudes to behavioral interventions targeted to reduce responsivity to drug cues during incubation (Li and Frantz, 2009, Li and Frantz, 2017, Madsen et al., 2017). Incubation of craving elicited by nicotine or sucrose-associated cues is also lower in rats with adolescent exposure, compared to adults (Counotte et al., 2014, Funk et al., 2016). While oxycodone incubation is similar by age onset, adolescent-exposed rats show a higher incubation slope (Altshuler et al. 2021). Despite evidence that adolescent rats are more sensitive to cocaine-associated contexts, few studies have examined the ability of adolescent-formed contextual associations to trigger incubation of craving. To bridge this gap, we used an ABRV contextual reinstatement model to conduct Coc-SA, EXT, and an early relapse test (T1) during adolescence. To examine potential impacts on incubation of contextual drug-seeking based on age of drug exposure, we included a late relapse test after 15 days of abstinence (T15).