Supplementary Material for: Sex-dependent differences in the neural correlates of cocaine and emotional cue-reactivity in regular cocaine users and non-drug using controls: understanding the role of duration and severity of use

Introduction: The development of cocaine use disorder (CUD) in females is suggested to be more strongly related to neural mechanisms underlying stress-reactivity, whereas in males it is suggested to be more strongly related to neural mechanisms underlying drug cue-reactivity. Existing evidence, however, is based on neuroimaging studies that either lack a control group and/or have very small sample sizes that do not allow to investigate sex differences. Methods: The main objective of the current study was to investigate sex differences in the neural correlates of cocaine and negative emotional cue-reactivity within high-risk intranasal cocaine users (CUs: 31 males and 26 females) and non-cocaine-using controls (non-CUs: 28 males and 26 females). A region of interest (ROI) analysis was applied to test for the main and interaction effects of group, sex, and stimulus type (cocaine cues versus neutral cocaine cues and negative emotional cues versus neutral emotional cues) on activity in the dorsal striatum (DS), ventral striatum (VS), amygdala, and dorsal anterior cingulate cortex (dACC).
Results: There were no significant sex or group differences in cocaine cue-reactivity in any of the ROIs. Results did reveal significant emotional cue-reactivity in the amygdala and VS, but these effects were not moderated by group or sex. Exploratory analyses demonstrated that emotional cue-induced activation of the dACC and VS was negatively associated with years of regular cocaine use in female CUs, while this relationship was absent in male CUs.
Conclusions: While speculative, the sex-specific associations between years of regular use and emotional cue-reactivity in the dACC and VS suggest that, with longer years of use, female CUs become less sensitive to aversive stimuli, including the negative consequences of cocaine use, which could account for the observed “telescoping effect” in female CUs.

引言：现有研究提示，女性可卡因使用障碍（cocaine use disorder, CUD）的发生与应激反应相关的神经机制关联更为紧密，而男性则更与药物线索反应相关的神经机制相关。然而，现有证据均来自神经影像学研究，这些研究要么缺乏对照组，要么样本量极小，无法开展性别差异相关研究。
方法：本研究的核心目标为，在高风险经鼻吸食可卡因使用者（可卡因使用者组：31名男性、26名女性）与非可卡因使用对照组（非使用者组：28名男性、26名女性）中，探究可卡因与负性情绪线索反应的神经关联中的性别差异。本研究采用感兴趣区（region of interest, ROI）分析方法，检验组别、性别、刺激类型（可卡因线索vs.中性可卡因线索，负性情绪线索vs.中性情绪线索）对背侧纹状体（dorsal striatum, DS）、腹侧纹状体（ventral striatum, VS）、杏仁核以及背侧前扣带回皮层（dorsal anterior cingulate cortex, dACC）活动的主效应与交互效应。
结果：所有感兴趣区均未在可卡因线索反应中发现显著的性别或组别差异。研究结果确实在杏仁核与腹侧纹状体中发现了显著的情绪线索反应效应，但此类效应未受组别或性别的调节。探索性分析显示，在女性可卡因使用者中，情绪线索诱发的背侧前扣带回皮层与腹侧纹状体激活程度与规律吸食可卡因的年限呈负相关，而男性可卡因使用者中未发现该关联。
结论：尽管尚属推测，但规律吸食年限与背侧前扣带回皮层、腹侧纹状体的情绪线索反应之间的性别特异性关联提示，随着吸食年限的增加，女性可卡因使用者对厌恶性刺激（包括可卡因使用带来的负面后果）的敏感性会有所降低，这或许可以解释此前在女性可卡因使用者中观察到的病程缩短效应（telescoping effect）。