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 - PubMed (original) (raw)

K Xu et al. Transl Psychiatry. 2013.

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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Figures

Figure 1

Figure 1

Mean (and standard error) drug craving response (averaged across all time points) during each of the neutral (N), stress (S) and drug cue (T) conditions for the two OPRK1 rs6989250 genotypes is shown. The genotype-by-condition two-way interaction was significant (_P_=0.0056, Cohen's _d_=0.79). Carriers of the CG genotype showed markedly stronger craving when exposed to the stress condition compared with individuals with the CC genotype (_P_=0.0191, Cohen's _d_=0.82). There was no significant difference detected between the two genotype groups in either the neutral (_P_=0.0823) or drug cue conditions (_P_=0.678).

Figure 2

Figure 2

Mean (and standard error) plasma cortisol levels averaged across all time points in the neutral (N), stress (S) and drug cue (T) conditions for the OPRK1 rs6989250 genotype groups are shown. There was a significant genotype–condition interaction (_P_=0.0003, Cohen's _d_=1.01), with CG individuals showing higher cortisol levels during stress compared with the neutral and drug cue conditions (P<0.0001 for stress versus neutral Cohen's _d_=1.46; _P_=0.003, Cohen's _d_=1.04 for cue versus neutral), whereas CC individuals showed no stress-induced increases in cortisol compared with their cortisol responses in the drug cue and neutral conditions (_P_'s>0.05).

Figure 3

Figure 3

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 _χ_2=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.

Figure 4

Figure 4

Whole brain analysis of neural activation during (a) stress and (b) drug cue exposure in the CG group relative to the CC group. During the stress and drug cue relative to the neutral condition, the CG group showed increased activity in the hypothalamus, midbrain (ventral tegmental area and locus coeruleus), thalamus and cerebellum relative to the CC group. Additionally, the CG group displayed increased stress-induced activity in the right amygdala/hippocampus and periaqueductal gray (PAG) area of the midbrain compared with the CC group (P<0.05, whole-brain family-wise error (FWE) corrected). The blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in each significant cluster (Table 2) is displayed in bar graphs for each genotype group in (a) stress-neutral and (b) drug-neutral conditions (see Table 2 for _t_-values and Cohen's d). Coordinates are given in Montreal Neurological Institute (MNI) space.

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