4. DISCUSSION
In the past decade, increases in cocaine use in females have been
observed in comparison to males(Mustaquim et al. , 2021). There
are indications for sex differences in clinical profiles of persons with
CUD, such as psychiatric comorbidity and an accelerated progression to
compulsive use in female CUs(Fonseca et al. , 2021). Yet, the
exact neural mechanisms underlying sex differences in CUD remain poorly
understood with potential implications for the development of
sex-tailored treatment strategies(Orsini et al. , 2022).
Accordingly, the main objective of the current study was to investigate
sex-dependent differences in the neural activation of various regions of
interest (ROIs), including the dorsal striatum (DS), ventral striatum
(VS), amygdala, and dorsal anterior cingulate cortex (dACC), of both
cocaine and emotional cue reactivity within CUs and non-CUs.
In contrast to our main hypotheses, no sex-dependent differences in
cocaine or emotional cue reactivity were found when comparing CUs to
non-CUs. Exploratory analyses demonstrated that cocaine cue-induced
activation of the DS and amygdala was positively related to cocaine use
severity in female CUs, whereas in male CUs only a negative relationship
was observed between the cocaine-induced activation of the amygdala and
cocaine use severity. Finally, emotional cue-induced activation of the
dACC and VS was negatively related to years of regular use in female
CUs, whereas this relationship was positive for male CUs.
The lack of sex-dependent differences in cocaine cue and emotional
reactivity does not correspond with previous literature(Volkow et
al. , 2011; Potenza et al. , 2012; Zhang et al. , 2021). A
possible explanation is that the mean years of regular cocaine use in
the current study sample was 4.7 and 5.2 years for male and female CUs,
respectively. Previous studies consisted of a longer mean range from
11.3 and 8.4 years(Potenza et al. , 2012) to 18 and 20
years(Volkow et al. , 2011) in male and female CUs, respectively.
This discrepancy might be of significance, as years of regular cocaine
use has been suggested to be more centrally related to cocaine cue
reactivity than CUD diagnosis(Prisciandaro et al. , 2015).
While the current study’s main hypotheses for cocaine cue reactivity
were not confirmed, exploratory analyses revealed interesting findings.
First, a positive relationship was observed between cocaine cue
reactivity in the DS and cocaine use severity in female CUs, whereas no
relationship was observed in male CUs. This suggests that the salience
of cocaine cues in female CUs become more prominent as cocaine use gets
more severe, which is commensurate with the distinctive feature of
rewarding feelings of ‘wanting’ the drug in the later stages of
addiction(Everitt & Robbins, 2013). Second, results demonstrated a
positive relationship between cocaine cue reactivity in the amygdala and
cocaine use severity within female CUs, whereas a negative relationship
was observed in male CUs. This indicates that cocaine cues induce
stronger activation in the amygdala within female CUs when severity of
use is greater, whereas the opposite might be observed in male CUs.
Significantly, the amygdala is a key brain region in the brain
arousal/stress system that plays an important role in engaging the
transition and maintenance of dependence(Koob, 2009) and reinstating
cue-dependent drug seeking(Sharp, 2017), which could exacerbate the
transition to compulsive use in female CUs.
Furthermore, exploratory analyses revealed significant negative
relationships between emotional cue induced activation in the dACC and
VS and years of regular use within female CUs. Earlier research has
consistently demonstrated decreased neural response to emotional stimuli
in CUD(Goldstein et al. , 2009; Asensio et al. , 2010),
particularly among female CUs in the medial prefrontal cortex/ACC
region(Canterberry et al. , 2016). This attenuated response to
emotional cues is consistent with the impaired response inhibition and
salience attribution model(Ceceli et al. , 2022) in which
individuals devalue non-drug related rewards and negative stimuli that
leads to risky behaviors(Canterberry et al. , 2016) and poor
treatment outcome(Konova et al. , 2008). Moreover, the VS is
posited to play a pivotal role in mediating responses to aversive
stimuli(Konova et al. , 2008). Presumably this is due to the
“rewarding effects” of successfully avoiding aversive or punishing
events(Kim et al. , 2006; Oleson et al. , 2012), which has
been shown to promote future behavior in animals(Wenzel et al. ,
2015). Consistently, one human study demonstrated decreased activation
of the NAc during passive avoidance in response to aversive stimuli,
whereas greater activation of the NAc was found during active
avoidance(Levita et al. , 2012). Taken together, this indicates
that female CUs with more years of cocaine use assign less salience
towards negative emotional stimuli and are less able to actively avoid
aversive stimuli, primarily due to hypoactivation in the dACC and VS,
respectively.
While speculative, these exploratory findings suggest that female CUs
may become more amenable to positive reinforcement and compulsivity
(i.e., greater DS activity), and less amenable to negative reinforcement
(i.e., less dACC activity) as the addiction develops with greater
severity and more years of use. Together with reinstating cue-dependent
drug seeking (i.e., greater amygdala activity) and the diminished
ability to actively avoid averse stimuli (i.e., less VS, but also dACC
activity), this could create a double whammy for female CUs and make
them more prone to risky behavior as the addiction develops, which could
account for the observed “telescoping effect” in females(Fonsecaet al. , 2021).
Finally, whole brain analyses revealed significant emotional cue-induced
activation of the salience network, including the medial PFC, temporal
cortex and visual cortex. Moreover, emotional-cue induced activation of
the left insula was significantly stronger in CUs compared to non-CUs,
but no sex-dependent differences. This is inconsistent with earlier
research who demonstrated greater insula activity in female CUs compared
to male CUs when exposed to stress cues(Li et al. , 2005; Potenzaet al. , 2012). Potentially, this could be explained by the
particular representation of emotional cues, i.e., negative valence
pictures in the current study versus personalized stress imagery in
earlier studies(Li et al. , 2005; Potenza et al. , 2012).
Indeed, personalized cues potentially maximize cue reactivity, but
simultaneously lead to heterogeneity that limits generalizability and
interpretation(Ekhtiari et al. , 2022). Lastly, whole brain
analyses demonstrated that the left insula and amygdala were more
strongly activated in females compared to males in response to emotional
cues, but there were no significant sex-dependent differences between
CUs and non-CUs.
An important strength of the current study is its design to specifically
investigate sex differences in both cocaine and emotional cue-reactivity
in regular CUs and non-CUs. Specifically, the current study comprised a
relatively large sample in which all individuals met DSM-5 criteria for
CUD according to a self-report(First, 2015) and were matched on most
cocaine-use related variables. Yet, female CUs were associated with
earlier onset of regular cocaine use when compared to male CUs, but did
not differ in total years of regular use or use per month (in grams).
Another strength of the current study is that the negative emotional and
neutral cues were obtained from the OASIS database(Kurdi et al. ,
2017) and the cocaine cues were obtained from an earlier study (Kaaget al. , 2018) that facilitates replicability for future research.
Lastly, exploratory analyses were perfomed on the influence of menstrual
phase and the use of hormonal contraceptives as there is increasing
evidence that fluctuating sex hormones strongly influence processes of
positive and negative reinforcement(Voorhees et al. , 2012; Kokane
& Perrotti, 2020). In line with this we demonstrated that emotional cue
induced activation of the amygdala and dorsal striatum was moderated by
hormonal contraceptive use and menstrual phase, highlight the relevance
of including measures of menstrual phase and hormonal contraceptive use
in future studies.
One limitation of the current study is its cross-sectional design that
precludes the ability to make any conclusions about cause and effect
regarding the aforementioned relationships. Furthermore, the current
study did not perform a urine screening while participants were
instructed to abstain from cocaine use 24 hours prior to study
participation. This is important as cocaine metabolites can be detected
in urine up to six days after last use(Preston et al. , 2002),
which is much longer than its psychopharmacological effects.
Alternatively, the current study used the TLFB prior to the experiment
which is a highly reliable method to assess cocaine use(Robinsonet al. , 2014). Although several studies show a high concordance
between self-report and urine screening(Darke, 1998; Wilcox et
al. , 2013), it remains impossible to conclude that participants were
not (still) intoxicated or inebriated. Finally, it may be important to
conduct drug and emotional cue reactivity paradigms on separate days or
randomize these conditions in order to circumvent possible carryover
effects of reward and emotional cues .
To further establish the current findings, future research should take
into account duration and severity of use when conducting cue reactivity
paradigms by performing longitudinal and prospective research (e.g.,
ecological momentary assessments) in order to gain understanding in
sex-dependent trajectories in positive and negative reinforcement within
the development of CUD. Moreover, understanding sex differences in
neural mechanisms underlying CUD is clinically significant because of
differential treatment effects in both males and females(Orsini et
al. , 2022). For instance, guanfacine is able to elicit greater
reduction in stress- and cue-mediated cocaine craving in female CUs(Foxet al. , 2014) due to improvements in cognitive
control(Milivojevic et al. , 2017), whereas oxytocin has shown
promise in diminishing the stress response (i.e., less amygdala
activation) to cocaine cues in male CUs with a history of childhood
trauma, whereas it increased the stress response in female CUs with
childhood trauma(Joseph et al. , 2020).
In conclusion, the current study found no significant sex differences in
cocaine and emotional cue reactivity in regular CUs. Yet, it did
demonstrate a positive relationship between cocaine cue reactivity and
cocaine use severity and a significant negative relationship between
emotional cue reactivity and years of regular use in female CUs compared
to male CUs, thus indicating important sex differences in underlying
neural mechanisms in the development of CUD. It is important to keep
improving our understanding of sex differences in CUD due to its
implications for treatment efficacy in both males and females.