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A variant on the kappa opioid receptor gene (OPRK1) is associated with stress response and related drug craving, limbic brain activation and cocaine relapse risk.

Xu K, Seo D, Hodgkinson C, Hu Y, Goldman D, Sinha R - Transl Psychiatry (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT 06519, USA.

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.

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Related in: MedlinePlus

Log-rank survival analysis for abstinence versus cocaine relapse in the CG and CC genotype groups. The survival rate for the CG genotype group was significantly lower than for the CC genotype group (Log-rank χ2=5.242; P=0.0075). Within 14 days, only 10% individuals with the CG genotype remain abstinence of cocaine use; 45% individuals with the CC genotype remain abstinence. The Y axis shows the proportion of participants who did not relapse; the X axis shows the 90-day follow-up time period.
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fig3: Log-rank survival analysis for abstinence versus cocaine relapse in the CG and CC genotype groups. The survival rate for the CG genotype group was significantly lower than for the CC genotype group (Log-rank χ2=5.242; P=0.0075). Within 14 days, only 10% individuals with the CG genotype remain abstinence of cocaine use; 45% individuals with the CC genotype remain abstinence. The Y axis shows the proportion of participants who did not relapse; the X axis shows the 90-day follow-up time period.

Mentions: We compared the subsequent cocaine relapse rates during the 90-day follow-up period after discharge from inpatient treatment and research for the CG and CC groups. The CG group showed a significantly greater relapse risk than the CC group (Log-rank χ2=7.157; df=1; P=0.0075) (Figure 3). For example, the abstinence rate in the first 14 days was only 10% in the CG group but 45% in the CC group. Thus, individuals with a CG genotype were more likely to relapse and return to cocaine use than the CC group, suggesting that the OPRK1 rs6989250 SNP G allele may increase vulnerability to cocaine relapse.


A variant on the kappa opioid receptor gene (OPRK1) is associated with stress response and related drug craving, limbic brain activation and cocaine relapse risk.

Xu K, Seo D, Hodgkinson C, Hu Y, Goldman D, Sinha R - Transl Psychiatry (2013)

Log-rank survival analysis for abstinence versus cocaine relapse in the CG and CC genotype groups. The survival rate for the CG genotype group was significantly lower than for the CC genotype group (Log-rank χ2=5.242; P=0.0075). Within 14 days, only 10% individuals with the CG genotype remain abstinence of cocaine use; 45% individuals with the CC genotype remain abstinence. The Y axis shows the proportion of participants who did not relapse; the X axis shows the 90-day follow-up time period.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756290&req=5

fig3: Log-rank survival analysis for abstinence versus cocaine relapse in the CG and CC genotype groups. The survival rate for the CG genotype group was significantly lower than for the CC genotype group (Log-rank χ2=5.242; P=0.0075). Within 14 days, only 10% individuals with the CG genotype remain abstinence of cocaine use; 45% individuals with the CC genotype remain abstinence. The Y axis shows the proportion of participants who did not relapse; the X axis shows the 90-day follow-up time period.
Mentions: We compared the subsequent cocaine relapse rates during the 90-day follow-up period after discharge from inpatient treatment and research for the CG and CC groups. The CG group showed a significantly greater relapse risk than the CC group (Log-rank χ2=7.157; df=1; P=0.0075) (Figure 3). For example, the abstinence rate in the first 14 days was only 10% in the CG group but 45% in the CC group. Thus, individuals with a CG genotype were more likely to relapse and return to cocaine use than the CC group, suggesting that the OPRK1 rs6989250 SNP G allele may increase vulnerability to cocaine relapse.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT 06519, USA.

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.

Show MeSH
Related in: MedlinePlus