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Abstract
Stress increases drug craving and relapse risk. The kappa opioid receptor gene (OPRK1) mediates stress responses. Here, we examined whether the OPRK1 rs6989250 C>G affects stress-induced cocaine craving and cortisol responses, subsequent cocaine relapse risk and the neural response to stress using functional magnetic resonance imaging (fMRI) in cocaine dependence. Sixty-seven treatment-engaged, abstinent cocaine-dependent African-Americans were genotyped (CG: N=10; CC: N=57) and participated in a 3-day experiment in which they were exposed to personalized script-driven imagery of stress, drug cues and neutral scenarios, one condition per day, randomly assigned and counterbalanced across subjects. Repeated measures of craving and cortisol were obtained. The subjects were followed prospectively for 90 days to assess relapse risk. A follow-up preliminary fMRI experiment assessed neural responses to stress, drug cue and neutral conditions in matched CG (N=5) and CC (N=8) subgroups. We found greater stress-induced craving (P=0.019), higher cortisol during stress and cue relative to the neutral condition (P's<0.003), and increased cocaine relapse risk (P=0.0075) in the CG compared with the CC group. The CG relative to the CC group also showed greater activation of limbic and midbrain regions during stress and cues relative to the neutral condition with additional stress-induced activation in the right amygdala/hippocampus (P<0.05, whole-brain corrected). These results suggest that OPRK1 is associated with stress-induced craving and cortisol, hyperactive hypothalamus/thalamus–midbrain–cerebellum responses, and also associated with greater subsequent cocaine relapse risk. Future studies to replicate these findings in a larger sample size are warranted.
Highlights
Relapse to drug use is the central problem in the treatment of addiction.[1]
We examined whether the single-nucleotide polymorphism (SNP) rs6989250 C4G on the 50-regulatory region of OPRK1 affected stressinduced cocaine craving and cortisol in the laboratory and subsequent cocaine relapse risk
This study showed that the putative functional SNP in the 50-regulatory region of OPRK1 is associated with significantly higher stress-induced craving, cortisol responses and increases subsequent risk of cocaine relapse in an AfricanAmerican population with cocaine dependence
Summary
Relapse to drug use is the central problem in the treatment of addiction.[1]. It is well known that acute and chronic stress increases drug craving and contributes to high rates of addiction relapse.[2,3] the remarkable individual variation observed in stress and drug craving suggests that genetic variants may contribute to the differences in response to stress, craving and relapse risk.Converging evidence shows that the kappa opioid receptor (KOR) has an important role in mediating the stress response and in stress-related addictive processes.[4,5,6,7,8] Activation of the KOR through the administration of dynorphin, a KOR endogenous neuropeptide, produces stress aversive symptoms in rats.[6,7,9,10] Physical stress and social defeat elevate dynorphin levels,[11,12,13,14] suggesting that activation of the KOR system increases both the physical and psychological stress responses. Relapse to drug use is the central problem in the treatment of addiction.[1] It is well known that acute and chronic stress increases drug craving and contributes to high rates of addiction relapse.[2,3] the remarkable individual variation observed in stress and drug craving suggests that genetic variants may contribute to the differences in response to stress, craving and relapse risk. Stress and dysphoria are closely associated with craving and relapse risk.[2,17,18,19,20] Genetic variants of the prodynorphin gene are associated with negative emotions and alcohol dependence.[21] genetic variants of OPRK1 may modulate individual stress responses, stressinduced craving and the relapse risk associated with cocaine dependence
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