Abstract
The glutamate receptor, N-methyl D-aspartate 2A (GRIN2A) gene that encodes the 2A subunit of the N-methyl D-aspartate (NMDA) receptor was recently shown to be involved in the development of opiate addiction. Genetic polymorphisms in GRIN2A have a plausible role in modulating the risk of heroin addiction. An association of GRIN2A single-nucleotide polymorphisms (SNPs) with heroin addiction was found earlier in African Americans. To identify markers that contribute to the genetic susceptibility to heroin addiction, we examined the potential association between heroin addiction and forty polymorphisms of the GRIN2A gene using the MassARRAY system and GeneScan in this study. The frequency of the (GT)26 repeats (rs3219790) in the heroin addiction group was significantly higher than that in the control group (χ2 = 5.360, P = 0.021). The allele frequencies of three polymorphisms (rs1102972, rs1650420, and rs3104703 in intron 3) were strongly associated with heroin addiction (P<0.001, 0.0002, and <0.001, after Bonferroni correction). Three additional SNPs from the same intron (rs1071502, rs6497730, and rs1070487) had nominally significant P values for association (P<0.05), but did not pass the threshold value. Haplotype analysis revealed that the G-C-T-C-C-T-A (block 6) and T-T (block 10) haplotypes of the GRIN2A gene displayed a protective effect (P = <0.001 and 0.003). These findings point to a role for GRIN2A polymorphisms in heroin addiction among the Han Chinese from Shaanxi province, and may be informative for future genetic or neurobiological studies on heroin addiction.
Highlights
Heroin addiction is a chronically relapsing disease characterized by compulsive drug seeking, drug abuse, tolerance, and physical dependence
GRIN2A regulates reward-related associative learning, cognition, memory, and structural and behavioral plasticity in the context of drug addiction [13,14,15,16,21,25,26], suggesting that GRIN2A acts upon the brain’s reward system, which plays a key role in drug addiction
Our results provide direct evidence that a genetic change in GRIN2A is linked to heroin addiction in humans, and extends the list of variants that may affect the development of heroin addiction [4]
Summary
Heroin addiction is a chronically relapsing disease characterized by compulsive drug seeking, drug abuse, tolerance, and physical dependence. Several studies have shown that chronic administration of drugs of abuse, such as alcohol [17], methamphetamine [18], cocaine [19], and nicotine [20], alters the activity of GRIN2A in the brain, suggesting that the GRIN2A gene is an excellent candidate target for treatment of addiction disorders. These results indicate that glutamatergic transmission, through GRIN2A-containing NMDA receptors in the nucleus accumbens, probably contributes to the development of opiate addiction and confirms the hypothesis that subtype-selective NMDA receptor antagonists may be beneficial in the treatment of opiate addiction and withdrawal [21]
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