Lorcaserin modulation of semantic drug cue-elicited effective brain connectivity in persons with cocaine and opioid use disorders

Understanding the neural mechanisms of drug cue reactivity may improve understanding of therapeutic targets for substance use disorders (SUDs). Preclinical studies indicate that the serotonin (5-HT) 5-HT_2A receptor (5-HT_2AR) and 5-HT_2CR systems considerably but oppositely impact relapse vulnerability. Specifically, 5-HT_2AR antagonists and 5-HT_2CR agonists reduce drug-seeking behavior and reactivity to drug cues. Our previous neuroimaging study showed that mirtazapine (a non-selective 5-HT_2AR antagonist) can reduce the effective connectivity (EC) of the pathway from the anterior cingulate cortex (ACC) to the hippocampus. The EC of this pathway has been consistently found to be associated with attentional bias towards drug cues in individuals with SUDs. To extend this finding, we investigated the effect of lorcaserin (a 5-HT_2CR agonist) on the EC linked to attentional bias elicited by drug-related cues by employing dynamic causal modeling on functional magnetic resonance imaging data acquired during a drug-word Stroop task performed by 45 individuals diagnosed with SUDs. We observed a marginally positive correlation between the ACC → hippocampus EC and drug cue-related attentional bias at the pretreatment baseline. Furthermore, compared to the placebo condition, 7-day administration of lorcaserin reduced the ACC → hippocampus EC. Notably, these EC outcomes remained unaffected by factors such as handedness, presence of drug metabolites in urine, pretreatment urine drug screen, and the type of substance used. This study contributes further evidence of serotonergic regulation of the ACC → hippocampus EC, and the potential for this EC to be an early signal of target engagement for medication to treat SUDs.