OPRM1 gene variants modulate amphetamine-induced euphoria in humans

Abstract

The μ-opioid receptor is involved in the rewarding effects of not only opioids like morphine but also psychostimulants like amphetamine. This study aimed to investigate associations between subjective response to amphetamine and genetic polymorphisms and haplotypes in the μ-opioid receptor including the exonic variant rs1799971 (Asp40Asn). One hundred and sixty-two Caucasian volunteers participated in three sessions receiving either placebo or d-amphetamine (10 and 20 mg). Associations between levels of self-reported Euphoria, Energy and Stimulation [Addiction Research Center Inventory 49-item questionnaire (ARCI-49)] after d-amphetamine ingestion and polymorphisms in OPRM1 were investigated. The intronic single nucleotide polymorphisms (SNPs) rs510769 and rs2281617 were associated with significantly higher ratings of Euphoria, Energy and Stimulation after 10 mg amphetamine. Feelings of Euphoria, Energy and Stimulation were also found to be associated with a two-SNP haplotype formed with rs1799971 and rs510769 and a three-SNP haplotype formed with rs1918760, rs2281617 and rs1998220. These results support the hypothesis that genetic variability in the μ-opioid receptor gene influences the subjective effects of amphetamine and may suggest new strategies for prevention and treatment of psychostimulant abuse.

Figure 1

Genomic structure of OPRM1 gene, mapped to chromosome 6, is shown to scale including 4 exons spanning 207.6 kb as well as results of linkage disequilibrium analyses: D’ values of single nucleotide polymorphisms along the OPRM1 gene, illustrating two haplotype blocks. D’ values were calculated by Haploview version 4.0.

Figure 2

Mean±SEM peak change scores on Euphoria and Stimulation (ARCI) in the three genotype groups at rs510769 after Placebo, 10 and 20 mg of amphetamine. Amphetamine (10 mg) increased Euphoria and Stimulation more in the rs510769A/G and G/G group than in the 510769A/A group. (*Significant drug × genotype interaction, Two-way ANOVA, not significant after adjustment for multiple testing). **Post hoc one-way ANOVA multiple comparisons between genotypes with Bonferroni correction p<0.05).

Figure 3

Mean±SEM peak change scores on Euphoria and Energy (ARCI) in the two genotype groups at rs2281617 (C/C: N=121; C/T and T/T: N=41) after Placebo, 10 and 20 mg of amphetamine. After 10mg of amphetamine (10 mg) the rs2281617C/C group reported greater increases in Euphoria, Energy and Stimulation and lower levels of Sedation compared to the 2281617C/T and T/T group. (*Significant drug × genotype interaction, two-way ANOVA, not significant after adjustment for multiple testing). **Post hoc one-way ANOVA multiple comparisons between genotypes with Bonferroni correction p<0.05).

Figure 4

Time courses of Euphoria, Energy, Stimulation and Sedation (ARCI) after 10 mg of amphetamine administration for the rs2281617 groups. The rs2281617C/C group reported a significantly greater increase in Euphoria and Energy compared to the T/T and C/T group in post hoc analyses (one-way ANOVA/ANCOVA). Post hoc analyses were not carried out for Stimulation and Sedation, as both scales were not significantly associated with rs2281617 genotype groups in primary analyses (two-way ANOVA/ANCOVA). Data are mean (SEM) ratings as change from predrug baseline. The groups did not significantly differ on baseline scores. (**p<0.01).