Oxytocin moderates corticolimbic social stress reactivity in cocaine use disorder and healthy controls

Abstract

Social stress can contribute to the development of substance use disorders (SUDs) and increase the likelihood of relapse. Oxytocin (OT) is a potential pharmacotherapy that may buffer the effects of social stress on arousal and reward neurocircuitry. However, more research is needed to understand how OT moderates the brain's response to social stress in SUDs. The present study examined the effect of intransasal OT (24 IU) versus placebo (PBO) on corticolimbic functional connectivity associated with acute social stress in individuals with cocaine use disorder (CUD; n = 67) and healthy controls (HC; n = 52). Psychophysiological interaction modeling used the left and right amygdala as seed regions with the left and right orbitofrontal and anterior cingulate cortex as a priori regions of interest. Moderators of the OT response included childhood trauma history and biological sex, which were examined in independent analyses. The main finding was that OT normalized corticolimbic connectivity (left amygdala-orbitofrontal and left amygdala-anterior cingulate) as a function of childhood trauma such that connectivity was different between trauma-present and trauma-absent groups on PBO, but not between trauma groups on OT. Effects of OT on corticolimbic connectivity were not different as a function of diagnosis (CUD vs HC) or sex. However, OT reduced subjective anxiety during social stress for CUD participants who reported childhood trauma compared to PBO and normalized craving response as a function of sex in CUD. The present findings add to some prior findings of normalizing effects of OT on corticolimbic circuitry in individuals with trauma histories and provide some initial support that OT can normalize subjective anxiety and craving in CUD.

Keywords: Amygdala; Anxiety; Childhood trauma; Craving; Montreal imaging stress task; Orbitofrontal cortex.

Fig. 1

Amygdala-Anterior Cingulate Cortex (ACC) connectivity results. The y-axis shows the parameter estimate for the psychophysiological interaction (PPI) of Task v. Practice contrast x Right/Left amygdala seed time series. The Task v. Practice contrast is the average connectivity over the two runs of the Montreal Imaging Stress Test (MIST) that followed experimenter feedback. (A) Main effect of diagnosis for the right amygdala seed (shown in red on inset) and ACC region of interest (ROI, shown in blue on inset). The cocaine use disorder (CUD) group shows negative connectivity whereas the healthy control (HC) group shows positive connectivity. (B) Main effect of diagnosis for the left amygdala seed (shown in red on inset) and ACC ROI (shown in blue on inset). The cocaine use disorder (CUD) group shows positive connectivity whereas the HC group shows negative connectivity. (C) Trauma Group × Treatment interaction for left amygdala seed and ACC ROI (see inset for panel B). Trauma-absent and trauma-present groups show significantly different connectivity on placebo (PBO) treatment, but not on oxytocin (OT) treatment. Error bars reflect standard error of the mean. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Amygdala-Orbitofrontal Cortex (OFC) connectivity results. The y-axis shows the parameter estimate for the psychophysiological interaction (PPI) of Task versus Practice contrast x Left amygdala seed time series. The Task v. Practice contrast is the average connectivity over the two runs of the Montreal Imaging Stress Test (MIST) that followed experimenter feedback. (A) Trauma Group × Treatment interaction for left amygdala seed (shown in red on inset) and left OFC region of interest (ROI, shown in green on inset). Trauma-absent and trauma-present groups show significantly different connectivity on placebo (PBO) treatment, but not on oxytocin (OT) treatment. (B) Trauma Group × Treatment interaction for left amygdala seed (shown in red on inset) and right OFC ROI (shown in green on inset). Trauma-absent and trauma-present groups show significantly different connectivity on PBO treatment, but not on OT treatment. Error bars reflect standard error of the mean. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Results for subjective ratings. (A) The significant Diagnosis x Trauma group × Treatment interaction for anxiety ratings. The y-axis is the average anxiety rating following experimenter feedback after the first and second MIST runs minus the baseline anxiety rating collected prior to the MIST. The cocaine use disorder (CUD) with trauma present (Trauma+) group on PBO showed significantly higher anxiety ratings than the CUD/Trauma + group on OT and compared to the healthy control (HC) trauma present group on PBO. (B) The significant Sex × Treatment interaction for cocaine craving ratings in the CUD group. The y-axis is the average craving rating following experimenter feedback after the first and second MIST runs minus the baseline craving rating collected prior to the MIST. Females and males show significantly different cocaine craving ratings on PBO but not on OT. Error bars reflect standard error of the mean.