1. INTRODUCTION
Cocaine is one of the most commonly used illicit substances around the world and causes severe economic, psychosocial, and psychiatric consequences(Mustaquim et al. , 2021). Generally, cocaine use disorder (CUD) is more prevalent in males than females, but this gap is slowly closing due to increased cocaine use in females from 2010 to 2019(Mustaquim et al. , 2021). Furthermore, there are several indications for sex differences in clinical profiles of CUD with significant implications for treatment(Fonseca et al. , 2021). For instance, in female cocaine users (CUs), there are higher rates of comorbid psychiatric mood disorders(Griffin et al. , 1989; Rounsaville et al. , 1991) whereas male CUs more often have comorbid alcohol abuse, attention deficit hyperactivity disorder and/or antisocial personality disorder (Griffin et al. , 1989; Rounsaville et al. , 1991). Accordingly, researchers have begun to explore the various mechanisms underlying sex differences in the development of substance use disorders (SUDs), including CUD(Fonsecaet al. , 2021).
One of the most frequently applied methods for understanding the underlying neurobiological mechanisms in SUDs are cue reactivity paradigms in which subjects are exposed to substance-related and/or emotional cues (e.g., pictures or videos) in addition to neutral cues during functional magnetic resonance imaging (fMRI) in order to identify brain regions that mediate the development, persistence and treatment of SUD(Courtney et al. , 2015). The number of neuroimaging cue reactivity studies has increased considerably during the last several decades according to a recent consensus paper (370 published studies through April 30, 2021)(Ekhtiari et al. , 2022). Yet, one recent systematic review identified only six neuroimaging studies to date that statistically evaluated sex differences in these neurobiological biomarkers in SUD(Nicolas et al. , 2022),despite the ubiquitous view that neurobiological sex differences in disease aetiology and neuropathology exist(Fonseca et al. , 2021; Nicolas et al. , 2022). Ultimately, this necessitates the need for hypothesis driven neuroimaging research into sex differences, primarily due to its implications in understanding the neurobiology of SUD(Courtney et al. , 2015; Fonseca et al. , 2021; Nicolaset al. , 2022; Orsini et al. , 2022) and developing sex-tailored treatment designs.
There is increasing evidence of sex-specific involvement of corticostriatal-limbic brain regions during the processing of cocaine or emotional cues(Li et al. , 2005; Volkow et al. , 2011; Potenza et al. , 2012; Canterberry et al. , 2016). More specifically, hyperactivation of the striatum, medial PFC, dorsal ACC and amygdala in response to drug cues have been reported in male CU’s, while hypoactivation of these regions is generally found in female CUs (Kilts et al. , 2004; Volkow et al. , 2011; Potenza et al. , 2012; Smith et al. , 2023). Similarly, hyperactivation of these prefrontal-limbic regions in response to negative emotional cues have been demonstrated in female CUs, while hypoactivation has been demonstrated in male CUs (Li et al. , 2005; Potenza et al. , 2012). While not all research findings are consistent (Canterberryet al. , 2016; Smith et al. , 2023), the overall finding is that male CUs, compared to female CUs demonstrated hyperactivation of the limbic corticostriatal brain regions, including the dorsal (DS) and ventral striatum (VS), dorsal ACC and amygdala, in response to cocaine related cues, while female CUs compared to male CUs demonstrate hyperactivation of these regions in response to negative emotional or stress-related cues(Nicolas et al. , 2022).
Nevertheless, results from previous studies should be taken with caution due to numerous identified limitations, including heterogeneity in cue reactivity paradigms (i.e., stress imagery(Li et al. , 2005; Potenza et al. , 2012), drug/emotional-related pictures(Canterberry et al. , 2016; Zhang et al. , 2021) or video’s(Volkow et al. , 2011), uneven male to female ratios(Liet al. , 2005; Volkow et al. , 2011; Zhang et al. , 2021), a lack of control groups(Li et al. , 2005; Volkow et al. , 2011; Zhang et al. , 2021), and small samples sizes(Liet al. , 2005; Volkow et al. , 2011; Tuit et al. , 2013; Canterberry et al. , 2016; Kober et al. , 2016; Zhanget al. , 2021) that are considered well below the recommended number needed for reproducibility of results in fMRI articles(Ekhtiariet al. , 2022). Therefore, the main objective of the current study was to investigate sex-dependent differences in the neural correlates of cocaine and (negative) emotional cue reactivity within CUs and non-CUs, within VS, DS, amygdala and dACC. In line with previous research, it was hypothesized that male CUs, compared to female CUs and non-drug using controls, would show stronger activation of the VS, DS, amygdala and dACC in response to cocaine-related cues, whereas female CUs compared to male CUs and non-drug using controls, would show stronger activation of these regions to negative emotional cues . A secondary objective was to investigate whether there was a sex-specific relationship between cocaine use characteristics and emotional and cocaine-cue induced activation of these brain regions. It was hypothesized that cocaine use characteristics (use per month, severity of use, onset age and duration of regular use) were specifically related to cocaine-cue related activation of the VS, DS, amygdala and dACC in male CUs, whereas these characteristics where specifically related to emotional cue-related activation of these regions in female CUs. Lastly, there is increasing evidence that fluctuating sex hormones in natural cycling women and synthetic hormones in women that use hormonal contraceptives, strongly influence processes of positive and negative reinforcement(Voorheeset al. , 2012; Kokane & Perrotti, 2020). Therefore several exploratory analyses were performed to investigate the effect of menstrual phase and hormonal contraceptive use on emotional and cocaine cue reactivity of which the methods and results are described in the supplementary material.