Genetic vulnerability to substance dependence

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Development of substance dependence and substance-induced psychoses should be influenced by not only pharmacological action of each substance but also individual genetic background. Therefore, I examined genetic risk and negative risk factors for methamphetamine dependence and/or psychosis, which has been epidemic in Japan after the World War II and social serious problems. Subjects were 198 Japanese patients with methamphetamine dependence (including 164 with both of dependence and psychosis) and age-and gender-matched healthy controls.Dopamine transporters are primary site of methamphetamine action in the brain, which is encoded by the hDAT1 gene. Four exonic polymorphisms have been registered in the NCBI database, and were analyzed. Although the hDAT1 gene did not associated with susceptibility to methamphetamine dependence or psychosis, a VNTR polymorphisms in the 3' UTR region was associated with prognosis of methamphetamine psychosis. Patients with 9 or fewer repeat allele of the … More VNTR showed more prolonged psychosis than those with 10 or more repeat allele. Odds ratio was so strong as 4.24.Pharmacological dopamine D2 receptors are considered as effective sites of dopamine release by methamphetamine. They are classified genetically into three subtypes, D2, D3 and D4 receptors encoded by the DRD2, DRD3 and DRD4 gene, respectively. It was found that patients with A1/A1 genotype of TaqIA polymorphism of the DRDZ gene showed significantly longer latency to onset of psychosis, less prolonged psychosis and less spontaneous relapse of psychosis. In addition, patients with -141del allele of the promoter region of the DRD2 gene showed significantly shorter latency from initial consumption to onset of psychosis. Ser9Gly polymorphism of the DRD3 gene, 521C>T or VNTR of 48 bp-repaet of the DRD4 gene did not associated with susceptibility of methamphetamine dependence or clinical aspects of the psychosis.Besides dopamine-related genes, the prodynorphine gene, precursor of opioid peptides such as dynorphins, was analyzed. A functional polymorphism of 68 bp-repeat VNTR in the promoter region was found to be associated with methamphetamine dependence. Three or four repeat-alleles, which have higher transcription activity of the gene, were a strong risk factor for development of dependence. The DRP-2 gene, which has discovered recently to be risk factor of schizophrenia, did not associated with methamphetamine dependence or psychosis. Less