br Introduction Despite a legacy

Introduction Despite a legacy of being characterized by “storm and stress” (Hall, 1904), there continues to be great controversy regarding whether decision-making in adolescence is inherently adaptive or harmful (Mills et al., 2014). Existing empirical data have generally fallen toward the side of risk, as captured by several prevailing theories of adolescent neurodevelopment [e.g., “dual process” (Somerville et al., 2010); “triadic” (Ernst, 2014)]. Broadly, these theories suggest a developmental imbalance between neural reward and control systems that arises because subcortical reward circuitry reaches maturity earlier than frontally mediated executive control regions (Steinberg, 2010; Galvan, 2014). This developmental pattern may contribute to differences in adolescent decision-making, particularly if there is an opportunity for reward (Galvan et al., 2007; Chung et al., 2011). While experimentation with substances is within the realm of typical adolescent behavior (Shedler and Block, 1990), there is some concern that substance use may exacerbate and/or enhance risks associated with the developing Deacetylase Inhibitor Cocktail (e.g., Squeglia et al., 2009; Lubman et al., 2007). Importantly, despite the prevalence of substance use during adolescence, the relationship between substance use and reward processing in the adolescent brain is not fully understood (Geier, 2013). However, given the well-established link between substance use and altered reward circuitry in adults (Volkow et al., 2003), there is reason to believe that substance use during adolescence may interact with developing reward processing substrates. One challenge in adolescent addiction research is that youth tend toward polysubstance use, using different substances together, often based on availability (Moss et al., 2014). American adolescents tend to abuse three substances: alcohol (75.6%), cannabis (48.6%), and tobacco (48.1%) (Kann et al., 2014). Despite the established use and clustering of these substances, most neuroimaging studies have examined only one, or at maximum two, substance per evaluation. This is problematic from a neural-circuitry perspective as prior studies revealed different patterns of brain response for single- vs. poly-substance using youth (i.e., alcohol-only, cannabis-only vs. alcohol+cannabis; e.g., Jacobus et al., 2013; Bava et al., 2009). Moreover, although research has begun to address co-occurring alcohol and cannabis use, few studies included tobacco. This is important given the possible impact of tobacco on the developing brain and on subsequent problem alcohol and cannabis use (Whelan et al., 2014). Thus, in a comprehensive model of adolescent reward processing, it is crucial to evaluate how these three substances interact with developing reward neurocircuitry; to our knowledge, this has not yet been done. In line with adult research (e.g., Knutson et al., 2001a; Abler et al., 2006), examinations of reward processing in adolescent substance users have focused on the nucleus accumbens (NAcc). This structure receives dopaminergic input from the ventral tegmental area (VTA) in response to reinforcing stimuli (Spanagel and Weiss, 1999). During adolescence, the NAcc is highly responsive to rewards (Galvan et al., 2006; Ernst et al., 2005). This may stem from naturally occurring developmental changes in dopaminergic functioning, including increased dopamine receptor expression in the NAcc and greater striatal dopamine release during adolescence (Galvan, 2010; Laviola et al., 2003; Tarazi et al., 1998). These normative changes in NAcc functioning and reward sensitivity may impact the development and maintenance of addiction (Volkow and Baler, 2014). Indeed, during adulthood, the ventral striatum (VS), which encompasses the NAcc, mediates the reinforcing effects of substances of abuse (Robinson and Berridge, 2000; Everitt and Robbins, 2005; Wise and Dopamine, 2004). Further, reward-related NAcc activation is associated with increased willingness to take risks (Knutson et al., 2008; Knutson and Greer, 2008). Individuals who experience greater VS/NAcc-mediated reward responses may thus be reinforced for engaging in risky and immediately rewarding behaviors such as substance use. Specifically, greater trait impulsivity has been observed in several studies of adolescent substance use (Stautz and Cooper, 2013; Fernández-Artamendi et al., 2015). Further, impulsivity is associated with greater reward sensitivity among substance users (Bjork et al., 2008). Thus, heightened reward sensitivity in the VS/NAcc may sustain problem substance use, potentially via amplifying the value of substance-related rewards in adolescents (and particularly among those with high impulsivity) (Karoly et al., 2013; Koob and Volkow, 2010).