Methamphetamine (MAP) is one of the most frequently used illegal substances in Japan, and family and twin studies have suggested that genetic factors contribute to psychostimulant dependence, including MAP dependence. Organic cation transporter 3 (OCT3) has been reported to be involved in the disposition of MAP as well as MAP-induced behavioral changes in animals. Moreover, SLC22A3 (which encodes OCT3) is a candidate gene for MAP dependence because it is located within a chromosomal region associated with substance dependence.
Using 96 healthy control subjects, linkage disequilibrium (LD) within the SLC22A3 was investigated, and 5 single-nucleotide polymorphisms (SNPs) were selected as haplotype tag SNPs to search for an association with MAP dependence. Single-marker analyses and haplotype analyses of these SNPs were performed in 213 subjects with MAP dependence and 443 healthy controls.
SLC22A3 polymorphisms were not significantly associated with MAP dependence in any of the single-marker and haplotype analyses. When subjects with MAP dependence were divided into polysubstance and single-MAP users, genotype and allele frequency of SNP2 (p=0.024, p=0.011, respectively), allele frequency of SNP3 (p=0.037), and haplotypic frequencies for these 2 SNPs (p=0.0438) differed significantly between groups.
These results suggest that polymorphisms of SLC22A3 are related to the development of polysubstance use in Japanese patients with MAP dependence.
"Such findings revealing a synergic action of OCT and DAT blockade on DA release in the nucleus accumbens have important implications for the understanding of drug relapse in humans. Consistent with this synergistic mechanism, a correlation was found previously between single nucleotide polymorphisms in the OCT3 gene and the development of polysubstance use in patients with methamphetamine dependence (Aoyama et al., 2006). 4. Other functions in the brain "
[Show abstract][Hide abstract] ABSTRACT: Organic cation transporters (OCTs) are polyspecific facilitated diffusion transporters that contribute to the absorption and clearance of various physiological compounds and xenobiotics in mammals, by mediating their vectorial transport in kidney, liver or placenta cells. Unexpectedly, a corpus of studies within the last decade has revealed that these transporters also fulfill important functions within the brain. The high-affinity monoamine reuptake transporters (SERT, NET and DAT) exert a crucial role in the control of aminergic transmission by ensuring the rapid clearance of the released transmitters from the synaptic cleft and their recycling into the nerve endings. Substantiated evidence indicate that OCTs may serve in the brain as a compensatory clearance systems in case of monoamine spillover after high-affinity transporter blockade by antidepressants or psychostimulants, and in areas of lower high-affinity transporter density at distance from the aminergic varicosities. In spite of similar anatomical profiles, the two brain OCTs, OCT2 and OCT3, show subtle differences in their distribution in the brain and their functional properties. These transporters contribute to shape a variety of central functions related to mood such as anxiety, response to stress and antidepressant efficacy, but are also implicated in other processes like osmoregulation and neurotoxicity. In this review, we discuss the recent knowledge and emerging concepts on the role of OCTs in the uptake of aminergic neurotransmitters in the brain and in these various physiological functions, focusing on the implications for mental health.
[Show abstract][Hide abstract] ABSTRACT: Organic cationic transporter 3 (OCT3, SLS22A3) has only recently emerged as one of the regulators of monoaminergic neurotransmission, which plays a critical role in the pathogenesis of depression and is a potential new antidepressant drug target. OCT3 single-nucleotide polymorphisms (SNPs) have been investigated for their association with psychiatric disorders such as methamphetamine use disorder and obsessive-compulsive disorder in children and adolescents, but not depression. This study was designed to evaluate the allele frequencies of seven OCT3 SNPs in a US Caucasian depressed population and compare these frequencies with a control group of nondepressed subjects. Informed consent and a DNA sample were obtained from 157 subjects and analysis was performed using real-time PCR. Allele and genotype frequencies were compared using a t-test and the Pearson chi-square analysis, respectively. There were no significant differences in OCT3 allele or genotype frequencies between the depressed and non-depressed groups for all seven SNPs evaluated.
"For GLTY1 rs2248829 conferred a protective effect (OR ¼ 0.72, P ¼ 0.04) but rs2486001 conferred a significant risk (OR ¼ 1.67, P ¼ 0.0002) [Morita et al., 2008]. For SLC22A3 markers rs3106164 and rs4709426 conferred a significant protective (OR ¼ 0.75, P ¼ 0.03) and risk (OR ¼ 1.29, P ¼ 0.03) effect, respectively [Aoyama et al., 2006]. In addition, GABRG2 marker rs211013 [Lin et al., 2003] and the GSTM1 gene deletion [Koizumi et al., 2004] were found to be significantly associated with an METH use disorder in females at the genotypic level but these findings did not translate to the allelic level, suggesting a mechanism of action other than additive. "
[Show abstract][Hide abstract] ABSTRACT: Efforts to understand the biological processes that increase susceptibility to methamphetamine (METH) use disorders (i.e., abuse, dependence, and psychosis) have uncovered several putative genotypic variants. However, to date a synthesis of this information has not been conducted. Thus, systematic searches of the current literature were undertaken for genetic-association studies of METH use disorders. Each gene's chromosomal location, function, and examined polymorphic markers were extracted. Frequencies, odds ratios and 95% confidence intervals for risk alleles, as well as sample size and power, were calculated. We uncovered 38 studies examining 39 genes, of which 18 were found to have a significant genotypic, allelic, and/or haplotypic association with METH use disorders. Three genes (COMT, DRD4, and GABRA1) were associated with METH abuse, nine (ARRB2, BDNF, CYP2D6, GLYT1, GSTM1, GSTP1, PDYN, PICK1, and SLC22A3) with METH dependence, two (AKT1 and GABRG2) with METH abuse/dependence, and four (DTNBP1, OPRM1, SNCA, and SOD2) with METH psychosis. Limitations related to phenotypic classification, statistical power, and potential publication bias in the current literature were noted. Similar to other behavioral, psychiatric, and substance use disorders, the genetic epidemiology of METH use disorders is complex and likely polygenic. National and international collaborative efforts are needed to increase the availability of large population-based samples and improve upon the power to detect genetic associations of small magnitude. Further, replication of the findings reviewed here along with further development of more rigorous methodologies and reporting protocols will aid in delineating the complex genetic epidemiology of METH use disorders.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2009; 150B(8):1025-49. DOI:10.1002/ajmg.b.30936 · 3.42 Impact Factor
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