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.