Smoked cocaine (SC) represents a major health risk among vulnerable populations in Latin America (Castaño, 2000, Castilla et al., 2020; Poder Judicial de la Ciudad de Buenos Aires, 2016). SC has a higher potential for Dependence than other slower routes of administration, such as insufflated cocaine (IC), as the former facilitates reinforcement and induces neuroplasticity changes in the reward system more easily (Allain et al., 2015, Oliveira et al., 2018, Samaha and Robinson, 2005). Our previous research has shown that, while overall cocaine Users exhibit executive-flexibility deficits measured by an extensive battery of cognitive tasks, attentional-executive impairments manifest solely in individuals with SC dependence (SCD), distinct from individuals with IC dependence (ICD) (de la Fuente et al., 2021). These findings align with clinical observations of heightened cognitive deficits in SC (Oliveira et al., 2018), alongside structural data indicating reduced gray matter density in the bilateral dorsal caudate in SCD compared to ICD (de la Fuente et al., 2021). However, the neurophysiological underpinnings of these deficits remain unexplored. To further define this subtle attentional-executive distinction, in this work we measured well-established attentional event-related potentials (ERPs), -which have been associated with substance use (Anderson et al., 2011; Biggins et al., 1997; Euser et al., 2012; Herning et al., 1994)-, on Users who differed only in the route of administration. By employing state-of-the-art attentional ERPs from oddball paradigm and a comprehensive attentional-executive neuropsychological assessment, we aimed to better understand the neural correlates of these cognitive deficits.

Three-oddball paradigms elicit the mismatch negativity (MMN), P3a and P3b components, reflecting pre-attentional, bottom-up, and top-down attentional processes, respectively (Conroy and Polich, 2007, Gooding et al., 2008, Heldmann et al., 2019, Hsieh et al., 2021). In passive tasks, infrequent stimuli evoke the MMN, unexpected or non-target stimuli evoke the P3a -with amplitude enhanced by the stimulus's salience-, and expected or target stimuli elicit the P3b, indicating attentional and executive processes (Carrasco, 2011, Desimone and Duncan, 1995, Friedman et al., 2001, Näätänen et al., 2007, Polich, 2007). In the context of neutral stimuli, studies have consistently shown bottom-up and top-down deficits signed by reduced P3a and P3b in Users of stimulants (Iwanami et al., 1998) and other drugs (Harper et al., 2021, Houston and Schlienz, 2018, Jurado-Barba et al., 2020, Maurage et al., 2007). When Users perform similarly to controls on cognitive tasks, they exhibit higher ERP amplitude, suggesting neural compensatory mechanisms (Campanella, 2021, Crego et al., 2012, Houston and Schlienz, 2018). Considering that factors such as drug-use level and drug type can impact the P3a and P3b (Polich and Criado, 2006), alongside the different cognitive profiles associated with SCD and ICD (de la Fuente et al., 2021), it is possible that these ERPs also vary according to the drug administration routes.

As attentional-executive deficits serve as a distinguishing factor between SCD and ICD, we aim to provide more clarity regarding the particular differences in the attentional process –encompassing both bottom-up and top-down aspects– that may arise due to variations in administration routes. For that reason, we conducted an analysis of attentional ERPs and hypothesized that SCD would exhibit reduced P3a/bottom-up processes, while both SCD and ICD would show reduced P3b/top-down processes. The impact of different cocaine administration routes on these attentional ERPs remains unclear, as most studies have not accounted for this relevant variable (Anderson et al., 2011, Campanella et al., 2019, Habelt et al., 2020, Wakim et al., 2021). Given the clinical relevance of these attentional ERPs in the context of substance use (Anderson et al., 2011, Biggins et al., 1997, Euser et al., 2012) and the distinct cognitive profiles associated with the route of administration, this study examines the differences in the P3a and P3b potential between SCD and ICD, and their relationship with neuropsychological performance in attentional tasks.