Associations of SLC6A3 gene VNTR polymorphism with the effects of extended-release naltrexone in alcohol dependence: Role of the opioid modulation of dopaminergic tonus

Background. The dopamine transporter gene SLC6A3 (DAT1) regulates synaptic dopamine levels by directly interacting with the opioid system in the mesolimbic reward pathway. Its VNTR polymorphism may modulate the response to the μ-opioid receptor antagonist naltrexone. Purpose of the study. To evaluate the effect of VNTR SLC6A3 on the efficacy of extended-release naltrexone (ER-N) in alcohol dependence (AD), with a focus on opioid-dopamine interaction as a key mechanism of action of the drug. Material and methods. In a 180-day prospective study, 100 Russian-speaking patients of Slavic origin with AD received monthly injections of PN. Genotyping of VNTR SLC6A3 was performed by PCR with electrophoretic detection of fragments. Validation of 20% of samples by sequencing (ABI 3500xl) confirmed 100% accuracy. The distribution of genotypes corresponded to Hardy-Weinberg equilibrium (χ²=1.32, p=0.25): 10R/10R (n=63), 9R/10R (n=33), 9R/9R (n=4). The duration of remission, adherence to therapy, frequency of relapses, dynamics of pathological craving (PACS scale), as well as phenotypic characteristics (craving structure and type of motivation) were assessed. Results. Carriers of the 9R/10R genotype had the most favourable clinical outcomes: 153.7±33.1 days (p=0.047), completion of therapy – 81.8% (p=0.048), decrease in craving according to PACS =-7.3±2.1 (p<0.001). The 9R/9R group (n=4) was not included in statistical comparisons due to its small size. The risk of relapse in carriers of ≥1 9R allele: OR=0.49 (95% CI: 0.24–0.99; p=0.048). Conclusion: VNTR SLC6A3 may modulate the efficacy of PN by influencing dopaminergic tone, which determines the sensitivity of the opioid system to blockade. Intermediate DAT expression in 9R/10R heterozygotes likely optimises naltrexone's ability to suppress opioid-induced dopamine release in the nucleus accumbens. The data obtained highlight the need to study the polygenic background (including OPRM1) for personalising therapy.