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.