Association between gene polymorphisms of SLC22A3 and methamphetamine use disorder
ABSTRACT 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.
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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.Pharmacology [?] Therapeutics 09/2014; 146. DOI:10.1016/j.pharmthera.2014.09.008 · 7.75 Impact Factor
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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.08/2011; 2011:161740. DOI:10.5402/2011/161740
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ABSTRACT: The organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission. Relative to wild-type (WT) animals, Oct3 knockout (KO) mice have displayed altered behavioral and neurochemical responses to psychostimulants such as amphetamine (AMPH) and methamphetamine. In the present study, both in vitro and in vivo approaches were utilized to explore potential mechanisms underlying the disparate neuropharmacological effects observed following AMPH exposure in Oct3 KO mice. In vitro uptake studies conducted in OCT3 transfected cells indicated that dextroamphetamine (d-AMPH) is not a substrate of OCT3. However, OCT3 was determined to be a high-capacity and low-affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). Inhibition studies demonstrated that d-AMPH exerts relatively weak inhibitory effects on the OCT3-mediated uptake of DA, NE, 5-HT, and the model OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide. The IC(50) values were determined to be 41.5 +/- 7.5 and 24.1 +/- 7.0 microM for inhibiting DA and 5-HT uptake, respectively, while 50% inhibition of NE and 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide uptake was not achieved by even the highest concentration of d-AMPH applied (100 microM). Furthermore, the disposition of d-AMPH in various tissues including the brain, liver, heart, kidney, muscle, intestine, spleen, testis, uterus, and plasma were determined in both male and female Oct3 KO and WT mice. No significant difference was observed between either genotypes or sex in all tested organs and tissues. Our findings suggest that OCT3 is not a prominent factor influencing the disposition of d-AMPH. Additionally, based upon the inhibitory potency observed in vitro, d-AMPH is unlikely to inhibit the uptake of monoamines mediated by OCT3 in the brain. Differentiated neuropharmacological effects of AMPHs noted between Oct3 KO and WT mice appear to be due to the absence of Oct3 mediated uptake of neurotransmitters in the KO mice.Journal of Neurochemistry 07/2010; 114(1):142-9. DOI:10.1111/j.1471-4159.2010.06738.x · 4.24 Impact Factor