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Publications (11)25.19 Total impact

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    ABSTRACT: The vesicular monoamine transporter 2 (VMAT2) translocates monoamine neurotransmitters from the neuronal cytoplasm into synaptic vesicles. Since VMAT2-/- mice die within a few days of birth, it is difficult to analyze the detailed VMAT2 functions using these mice. In this study, we generated human VMAT2 transgenic mice that expressed VMAT2 in noradrenergic neurons with the aim to rescue the lethality of VMAT2 deletion. The expression of human VMAT2 in noradrenergic neurons extended the life of VMAT2-/- mice for up to three weeks, and these mice showed severe growth deficiency compared with VMAT2+/+ mice. These results may indicate that VMAT2 expressed in noradrenergic neurons has crucial roles in survival during the first several weeks after birth, and VMAT2 functions in other monoaminergic systems could be required for further extended survival. Although VMAT2 rescue in noradrenergic neurons did not eliminate the increased morbidity and lethality associated with VMAT2 deletion, the extension of the lifespan in VMAT2 transgenic mice will enable behavioral, pharmacological and pathophysiological studies of VMAT2 function.
    Biochemical and Biophysical Research Communications 02/2013; · 2.28 Impact Factor
  • Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology 04/2011; 31(2):87-88.
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    ABSTRACT: Genetic factors are hypothesized to be involved in interindividual differences in opioid sensitivity. Inbred mouse strains that are genetically different and isogenic within each strain are useful for elucidating the genetic mechanisms underlying the interindividual differences in opioid-induced analgesia. We examined the effects of morphine in 10 inbred mouse strains, including wild-derived strains that have a wide range of genetic diversity, including BLG2, CHD, KJR, MSM, NJL, PGN2, and SWN. We also performed full sequencing of the 5' flanking region and exons of the mouse mu opioid receptor gene Oprm1 and analyzed the association between genotypes and phenotypes in these mice. The effects of morphine on locomotor activation and antinociception varied among the inbred strains. The nucleotide differences that cause amino acid substitutions were not found in the Oprm1 gene in the inbred strains analyzed in this study. In the 5' flanking region and 3' untranslated region of the Oprm1 gene, four highly variable regions containing novel short tandem repeat polymorphisms (GA, T, TA, and CA/CT) were identified. The GA, T, and TA repeat numbers were significantly associated with morphine-induced antinociception. These results suggest that the short tandem repeats in the 5' flanking and 3' untranslated regions of the mu opioid receptor gene are involved in interstrain differences in opioid sensitivity in mice. Wild-derived inbred mouse strains with different numbers of these repeats may be useful models for examining interindividual differences in opioid sensitivity.
    Pharmacogenetics and Genomics 12/2008; 18(11):927-36. · 3.61 Impact Factor
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    ABSTRACT: We examined the hyperthermic and lethal toxic effects of methamphetamine in dopamine transporter (DAT) and/or serotonin transporter (SERT) knockout (KO) mice. Methamphetamine (45 mg/kg) caused significant hyperthermia even in the mice with a single DAT gene copy and no SERT copies (DAT+/- SERT-/- mice). Mice with no DAT copies and a single SERT gene copy (DAT-/- SERT+/- mice) showed significant but reduced hyperthermia when compared to wild-type mice after methamphetamine. Surprisingly, DAT/SERT double KO mice exhibited a paradoxical hypothermia after methamphetamine. These results demonstrate that methamphetamine exerts a hyperthermic effect via DAT, or via SERT, in the absence of DAT. The selective norepinephrine transporter blocker (20 mg/kg nisoxetine) caused hyperthermia in DAT/SERT double KO mice, suggesting that the norepinephrine system is not responsible for methamphetamine-induced paradoxical hypothermia in the double KO mice. DAT gene deletion in mice strikingly increased LD50 of methamphetamine by 1.7-1.8 times that of wild-type mice, suggesting that the lethal toxic effect of methamphetamine is mainly dependent on DAT. Moreover, dissociation between hyperthermic and lethal toxic effects of methamphetamine in DAT single KO mice and DAT/SERT double KO mice suggest that hyperthermia is not a prerequisite for methamphetamine-induced lethality. Methamphetamine (45 mg/kg) significantly increased mRNA of interleukin-1beta, which is the major endogenous pyrogen, in the hypothalamus of wild-type mice but not in DAT/SERT double KO mice, which provides a partial mechanism of methamphetamine-induced paradoxical hypothermia. These results suggest that DAT and SERT are key molecules for hyperthermic and lethal toxic effects of methamphetamine.
    European Journal of Pharmacology 11/2007; 572(2-3):120-8. · 2.59 Impact Factor
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    ABSTRACT: The dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) play pivotal roles in the action of methamphetamine (MAP), including acute locomotor effects and behavioral sensitization. However, the relative impact of heterozygous DAT and VMAT2 knockouts (KOs) on the behavioral effects of MAP remains unknown. To evaluate the roles of DAT and VMAT2 in MAP-induced locomotor behavior, we examined locomotor activity and sensitization in heterozygous DAT KO (DAT+/-), heterozygous VMAT2 KO (VMAT2+/-), double heterozygous DAT/VMAT2 KO (DAT+/-VMAT2+/-), and wild-type (WT) mice. Acute 1 mg/kg MAP injection induced significant locomotor increases in WT and VMAT2+/- mice but not in DAT+/- and DAT+/-VMAT2+/- mice. Acute 2 mg/kg MAP significantly increased locomotor activity in all genotypes. Repeated 1 mg/kg MAP injections revealed a delayed and attenuated development of sensitization in DAT+/- and DAT+/-VMAT2+/- mice compared to WT mice and delayed development in VMAT2+/- mice. In repeated 2 mg/kg MAP injections, DAT+/- and DAT+/-VMAT2+/- mice showed delayed but not attenuated development of sensitization, while there was no difference in the onset of sensitization between VMAT2+/- and WT mice. In DAT+/-VMAT2+/- mice, all of MAP-induced behavioral responses were similar to those in DAT+/- but not VMAT2+/- mice. Heterozygous deletion of DAT attenuates the locomotor effects of MAP and may play larger role in behavioral responses to MAP compared to heterozygous deletion of VMAT2.
    Psychopharmacology 08/2007; 193(1):55-62. · 4.06 Impact Factor
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    ABSTRACT: The role of the delta-opioid receptor (OPRD1) in methamphetamine (MAP) addiction was investigated using association analysis between OPRD1 gene polymorphisms and MAP dependence/psychosis. DNA samples from Japanese patients with MAP dependence/psychosis were analyzed to find polymorphisms in OPRD1 gene exons and exon-intron boundaries. One novel single nucleotide polymorphism (SNP) in intron 1 and two SNPs in exon 3 were identified. The two SNPs in exon 3 were in linkage disequilibrium. No significant difference was observed in either genotypic or allelic frequencies of these SNPs between controls (n = 260) and MAP dependent/psychotic patients (n = 170). Global analyses using the three SNPs and subcategory analyses on clinical parameters also showed no significant differences. These results suggest that the OPRD1 gene variants may not be a factor in vulnerability to MAP dependence/psychosis.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2006; 141B(5):482-6. · 3.23 Impact Factor
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    ABSTRACT: Opioids have been suggested to affect feeding behaviour. To clarify the role of mu-opioid receptors in feeding, we measured several parameters relating to food intake in mu-opioid receptor knockout mice. Here, we show that the knockout mice had increased body weight in adulthood, although the intake amount of standard food was similar between the wild-type and knockout littermates. Serum markers for energy homeostasis were not significantly altered in the knockout mice. Hypothalamic neuropeptide Y mRNA, however, was higher in knockouts than in wild-type mice. Our results suggest that the up-regulated expression of neuropeptide Y mRNA might contribute to the increased weights of adult mu-opioid receptor knockout mice.
    Neuroreport 07/2006; 17(9):941-4. · 1.40 Impact Factor
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    ABSTRACT: CXBK mice, recombinant inbred mice derived from C57BL/6By and BALB/cBy progenitors, display reduced morphine-induced analgesia. Earlier we reported that CXBK mice expressed a reduced amount of the major transcript, MOR-1 mRNA, of the mu-opioid receptor gene. The CXBK MOR-1 mRNA contains a normal coding region and an abnormally long untranslated region. To identify the nucleotide-sequence difference between the CXBK MOR-1 mRNA and that of the progenitors, we first characterized the 3' untranslated region of the MOR-1 mRNA, which was largely unknown. A 3' rapid amplification of cDNA ends-PCR analysis revealed that the 3' untranslated region of the C57BL/6By MOR-1 mRNA was 10 181 nucleotides transcribed from an exon. Next, we compared the MOR-1 genes in C57BL/6By, CXBK, and BALB/cBy mice, and found a 5293 nucleotide insertion only in CXBK mice. The inserted sequence was a variant of the intracisternal A-particle elements that exist in the mouse genome at approximately 1000 sites. Reverse transcription-PCR analyses revealed that the intracisternal A-particle element was transcribed as a part of the CXBK MOR-1 mRNA. No other differences were found in the MOR-1 mRNA between CXBK and BALB/cBy mice, whereas 100 nucleotides differed between C57BL/6By and CXBK mice aside from the intracisternal A-particle insertion. Finally, CXBK mice displayed reduced morphine responses compared with BALB/cBy mice. Our data suggest that differences in the MOR-1 3' untranslated region appear to cause the CXBK phenotype. This genetic mechanism underlying the CXBK phenotype may provide good insight into the possible genetic mechanisms underlying individual differences in opioid sensitivity in humans.
    Pharmacogenetics and Genomics 07/2006; 16(6):451-60. · 3.61 Impact Factor
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    ABSTRACT: The mu-opioid receptor (MOR) plays a mandatory role in the action of most opioid drugs, such as morphine, fentanyl, and heroin. It has been revealed that a deficiency in the MOR gene (Oprm1) or a difference in the 3' noncoding region of the gene markedly affects the sensitivity of mice to opioids. As the 3' noncoding region of the human OPRM1 gene had not yet been characterized, in the present study we conducted 3'-rapid amplification of cDNA ends (3'RACE)-PCR and identified the 3' end of the human MOR-1 mRNA, the most abundant transcript among OPRM1 gene transcripts. The poly(A) signal was located at 13612-13617 nucleotides downstream from the stop codon in the OPRM1 gene. Reverse transcription PCR analyses showed that the region from the stop codon to the poly(A) signal was transcribed. In the 3'UTR, we identified 33 AU-rich regions and more than 300 putative transcription factor-binding sites. Furthermore, we compared the 3' noncoding regions of the human and mouse OPRM1/Oprm1 genes and found apparent homology. In Northern blotting with mouse brain mRNAs, a same-size band was detected by a probe for the MOR-1 coding region and by a probe for a mouse genome region corresponding to the human MOR-1 3'UTR. Since 3'UTRs affect gene expression, the present characterization of the 3' noncoding region in the human OPRM1 gene should lead to a better understanding of the mechanisms underlying OPRM1 gene regulation and individual differences in sensitivity to opioids.
    Gene 01/2006; 364:139-45. · 2.20 Impact Factor
  • Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology 11/2004; 24(5):316-8.
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    ABSTRACT: The uptake of L-serine, a nonessential amino acid known to be transported by the neutral amino acid transporter system ASC, was studied in primary cultures of rat neurons and astrocytes, and compared with that in human embryonic kidney (HEK293) cells transfected with rat ASCT1 cDNA. We first cloned neutral amino acid transporter ASCT1 from rat neurons in primary culture as a transporter candidate for L-serine uptake in the brain. The predicted amino acid sequence from rat ASCT1 exhibited significant homology with mouse and human ASCT1s. The amino acid sequence of rat ASCT1 was 92 and 84% identical to that of mouse and of human ASCT1, respectively. HEK293 cells expressing the rat ASCT1 cDNA showed a saturable dose-dependent and Na(+)-dependent increase in L-[(3)H] serine uptake by high affinity ( K(m) = 67 microM). The substrate selectivity of rat ASCT1 was the same as those of the mouse and human transporter. Northern blot analysis revealed that ASCT1 mRNA was ubiquitously expressed in the brain, with its highest concentration in the striatum and hippocampus. When the uptake of L -[(3)H] serine into rat primary neurons or astrocytes was compared with that of HEK293 cells expressing rat ASCT1 or rat ASCT2 cDNA, the inhibition profile of amino acids for the rat neurons quite resembled that for HEK293 cells expressing rat ASCT1. In contrast, the profile for rat astrocytes was a mixture of that for HEK293 cells expressing rat ASCT1 and that for the cells expressing rat ASCT2. Furthermore, L-[(3)H] serine uptake in neurons was fully Na(+)-dependent. ASCT1 mRNA was expressed in both primary neurons and astrocytes, whereas ASCT2 mRNA was expressed only in astrocytes, as determined by using RT-PCR with primers specific for the rat ASCT1 or rat ASCT2 transporter. Taken together, these findings indicate that ASCT1 predominantly contributes to the uptake of L-serine in primary neurons.
    Neuroscience Research 06/2004; 49(1):101-11. · 2.20 Impact Factor