Biomedical subjects

I Sora

Publications and source records attributed to I Sora.

At least 19 recordsLinked to original sources

PubMed2007

Possible association of beta-arrestin 2 gene with methamphetamine use disorder, but not schizophrenia.

Recent investigations suggest that the AKT/glycogen synthase kinase 3 (GSK3) signaling cascade may be associated with the pathophysiology of schizophrenia and methamphetamine (METH) use disorder. One important molecule related to this cascade is beta-arrestin 2 (ARRB2). We therefore conducted a genetic case-control association analysis of the gene for ARRB2 with schizophrenia and METH use disorder in a Japanese population (547 people with schizophrenia, 177 with METH use disorder and 546 controls). A possible association of 'tag single nucleotide polymorphisms (SNPs)' was found in METH use disorder (rs1045280: P(genotype) = 0.0118, P(allele) = 0.00351; rs2036657: P(allele) = 0.0431; rs4790694: P(genotype) = 0.0167, P(allele) = 0.0202), but no association was found with schizophrenia. We also evaluated the gene-gene interactions among ARRB2, AKT1, and GSK3B, which we previously reported for each of these diseases. However, no interaction was seen in our samples. This is the first association analysis of ARRB2, and our results indicate that ARRB2 may play a role in the pathophysiology of METH use disorder.

Adult↗

PubMed2006

Knockout of the mu opioid receptor enhances the survival of adult-generated hippocampal granule cell neurons.

Recent evidence suggests that mu opioid receptors (MOR) are key regulators of hippocampal structure and function. For example, exogenous MOR agonists morphine and heroin negatively impact hippocampal function and decrease adult hippocampal neurogenesis. Here we explored the role of MOR in the birth and survival of hippocampal progenitor cells by examining adult neurogenesis in mice that lack MOR. Adult male mice lacking exon 1 of MOR were injected with the S phase marker bromodeoxyuridine (BrdU) and killed either 2 hours or 4 weeks later to evaluate proliferating and surviving BrdU-immunoreactive (IR) cells, respectively, in the adult hippocampal granule cell layer. Wild-type (WT), heterozygote, and homozygote mice did not differ in the number of BrdU-IR cells at a proliferation time point. However, 4 weeks after BrdU injection, heterozygote and homozygote mice had 57% and 54% more surviving BrdU-IR cells in the hippocampal granule cell layer as compared with WT mice. A decrease in apoptosis in the heterozygote and homozygote mice did not account for the difference in number of surviving BrdU-IR cells since there were no alterations in number of pyknotic, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive, or activated caspase 3-IR cells compared with WT. In concordance with the increased numbers of granule cells maturing into neurons, heterozygote and homozygote mice had larger hippocampal granule cell layers and increased numbers of granule cells. These findings indicate that MOR may play a role in regulating progenitor cell survival and more generally encourage further exploration of how MOR activation can influence hippocampal structure and function.

Animals↗

PubMed2006

Association study of the dihydropyrimidinase-related protein 2 gene and methamphetamine psychosis.

Dihydropyrimidinase-related protein 2 (DRP-2 or DPYSL-2)mediates the intracellular response to collapsin, a repulsive extracellular guidance cue or axonal outgrowth. DRP-2 is also referred to as collapsin response mediator protein 2 (CRMP-2). We have previously demonstrated that the DRP-2 gene is associated with susceptibility to schizophrenia, but not to bipolar disorders. In addition, a genetic association was observed with paranoid-type schizophrenia, but not with hebephrenic-type schizophrenia. It has been well documented that repeated abuse of methamphetamine (METH) for a long period frequently produces psychotic symptoms, such as auditory hallucinations and delusions that are hardly distinguishable from those of paranoid-type schizophrenia. Therefore, we hypothesized that a certain genetic variant of the DRP-2 gene may affect individual vulnerability to the development of METH-induced psychosis. We examined the genetic association by a case-control method. The polymorphism *2236T>C in the 3' untranslated region of the DRP-2 gene, which has been shown to be a negative genetic risk factor for paranoid-type schizophrenia, was analyzed in 198 patients with METH psychosis and 221 corresponding healthy controls in a Japanese population. No significant association of the DRP-2 gene with METH psychosis was found. Neither did we find an association with the clinical phenotype of METH psychosis, such as the age of first consumption of METH, latency to development of psychosis after METH abuse, prognosis of psychosis after detoxification from METH use, complication of spontaneous relapse of psychosis without reconsumption of the drug, or multisubstance abuse status. These findings indicate that a genetic variant of the DRP-2 gene may not affect the risk of METH psychosis or any clinical phenotype of the disorder.

Adult↗

PubMed2006

Association study of the tumor necrosis factor-alpha gene and its 1A receptor gene with methamphetamine dependence.

Recent preclinical findings that repeated treatment with methamphetamine (METH) induced an increase in tumor necrosis factor-alpha (TNF-alpha) mRNA in some brain regions and that TNF-alpha blocked METH neurotoxicity and rewarding effects suggest TNF-alpha, a multifunctional pro-inflammatory cytokine, may be involved in METH dependence. We hypothesized that genetic polymorphisms of the TNF-alpha gene and its receptor genes may be associated with vulnerability to METH dependence. Genetic association of -308G>A and -857C>T in the promotor region of the TNF-alpha gene, and 36A>G in exon 1 of the TNF receptor 1A gene (TNFR-SF1A), were analyzed in patients with METH dependence (n = 185) and healthy controls (n = 221) in a Japanese population. No significant association of alleles or haplotypes of the TNF-alpha or TNFR-SF1A genes with METH dependence was found. Neither was any significant association of clinical phenotype with METH dependence found. These results suggest that genetic variations in the TNF-alpha gene and its receptor genes may not be involved in individual vulnerability to METH dependence.

Adult↗

PubMed2006

No association between CART (cocaine- and amphetamine-regulated transcript) gene and methamphetamine dependence.

Cocaine- and amphetamine-regulated transcript (CART) was originally discovered as a peptide that increased in the rat striatum after injection of a psychostimulant drug, such as cocaine or amphetamine, and is suggested to play potential roles in drug dependence. We tested the genetic association between the CART gene and methamphetamine (METH) dependence and/or psychosis. The subjects were 203 patients with METH dependence and 239 age- and gender-matched healthy controls. Two single nucleotide polymorphisms (SNPs) of the CART gene, -156A>G and IVS1 + 224G>A, were examined . There were no significant differences in genotype and allele distributions of the polymorphisms between patients with METH dependence and/or psychosis and controls. Neither were significant differences in subgroups of clinical phenotypes, for example, age at first consumption of METH, latency to onset of psychotic symptoms after the first consumption of METH, prognosis of psychosis after therapy, complication of spontaneous relapse to a psychotic state, or multisubstance abuse status, observed. The present findings suggest that the CART gene may not play a pivotal role in the development of METH dependence and psychosis, at least in a Japanese population.

Adult↗

PubMed2005

Haplotype association between GABAA receptor gamma2 subunit gene (GABRG2) and methamphetamine use disorder.

Psychostimulant use disorder and schizophrenia have a substantial genetic basis. Evidence from human and animal studies on the involvement of the gamma-aminobutyric acid (GABA) system in methamphetamine (METH) use disorder and schizophrenia is mounting. As we tested for the association of the human GABA(A) receptor gamma 2 subunit gene (GABRG2) with each diagnostic group, we used a case-control design with a set of 178 subjects with METH use disorder, 288 schizophrenics and 288 controls. First, we screened 96 controls and identified six SNPs in GABRG2, three of whom we newly reported. Next, we selected two SNPs, 315C>T and 1128+99C>A, as representatives of the linkage disequilibrium blocks for further case-control association analysis. Although no associations were found in either allelic or genotypic frequencies, we detected a haplotypic association in GABRG2 with METH use disorder, but not with schizophrenia. This finding partly replicates a recent case-control study of GABRG2 in METH use disorder, and thus indicates that GABRG2 may be one of the susceptibility genes of METH use disorder.

Adolescent↗

PubMed2004

No association found between the type 1 sigma receptor gene polymorphisms and methamphetamine abuse in the Japanese population: a collaborative study by the Japanese Genetics Initiative for Drug Abuse.

It has been suggested that individual genetic factors are involved in susceptibility to drug dependence and the manifestation of drug-induced psychosis. The aim of this study was to examine the relation between methamphetamine abusers/psychosis and the type 1 sigma receptor gene polymorphisms. Subjects comprised 143 MAP abusers and 181 healthy controls. Two polymorphisms in the type 1 sigma receptor gene, GC-241-240TT and A61C (Gln2Pro), were examined in the present study. No significant differences were observed in either polymorphism between healthy controls and MAP abusers/psychosis. In the subgroup analyses, the rate of CC genotype of A61C tended to be higher in MAP patients who had experienced spontaneous relapse without MAP use than in those who had not (P = .06, OR = 3.02 95%CI = 0.92-9.92). However, the level of this significant trend did not remain after the Bonferroni's multiple correction. This study suggests that type 1 sigma receptor gene is unlikely to play a major role in substance abuse liability and/or the development of MAP psychosis.

Adult↗

PubMed2004

No association is found between the candidate genes of t-PA/plasminogen system and Japanese methamphetamine-related disorder: a collaborative study by the Japanese Genetics Initiative for Drug Abuse.

In the central nervous system, tissue-plasminogen activator (t-PA)/plasmin system is involved in long-term synaptic plasticity and remodeling, and participates in rewarding effects of methamphetamine (MAP), by acutely regulating MAP-induced dopamine release in the nucleus accumbens. The aim of this study was to examine the relationships between the patients with MAP abusers/psychosis and the t-PA/plasminogen system genes. Subjects comprised 185 MAP abusers and 288 healthy controls. Four polymorphisms in the t-PA, plasminogen activator inhibitor, and plasminogen genes were examined in the present study. No significant differences were observed in each polymorphism between healthy controls and MAP abusers/psychosis. This study suggests that t-PA/plasminogen system is unlikely to be a major contributor to the substance abuse liability and/or the development of MAP psychosis.

Amphetamine-Related Disorders↗

PubMed2004

Changes in expression of the mouse homologues of KIAA genes after subchronic methamphetamine treatment.

Amphetamine abuse may be associated with adaptive changes in gene expression in the brain. In the present study, a newly developed cDNA array system comprising mouse KIAA (mKIAA) cDNA clones was used to examine the gene expression affected by chronic methamphetamine treatment. Approximately 800 mKIAA clones were blotted onto a nylon membrane and hybridized with 33P-labeled cDNA derived from mRNAs isolated from the whole brains of mice that had been treated daily with saline or methamphetamine (2 mg/kg, i.p.) for 2 weeks. The arrays displayed robust hybridization for almost all transcripts. The results obtained from five experiments were averaged, each performed with triplicate samples. Several clones were chosen as positive candidates for methamphetamine-induced changes; however, only Per2 and mKIAA0099 genes showed a significantly increased expression (P < .05). Subsequently, with the focus on the period-related proteins, the expression of these proteins in various parts of the rat brain were assessed by immunoblot analysis. Chronic administration of methamphetamine (8 mg/kg, i.p., for 10 days) caused increased Per2 protein expression in the hippocampus. Interestingly, chronic methamphetamine treatment at a lower dose (4 mg/kg, i.p., for 10 days) induced an increase in SCN circadian oscillatory protein (SCOP) expression, also in the hippocampus. These data suggest that long-lasting alterations of the period-related gene expressions in the hippocampus might play an important role in methamphetamine addiction.

Animals↗

PubMed2004

A polymorphism of DRD2 gene and brain atrophy in methamphetamine psychosis.

Our group, Ujike et al., recently reported that the A1 allele of TaqI A polymorphism of the dopamine receptor D2 (DRD2) gene, associated with transient psychosis, significantly differs from that of patients with prolonged psychosis in methamphetamine psychosis. Therefore, we examined the association between the TaqI A polymorphism of the DRD2 gene and the brain MRI view for patients with methamphetamine psychosis. The subjects underwent brain MRI scans using the FLAIR method. Genotyping was performed by PCR-RFLP methods using genomic DNA extracted from peripheral blood by the phenol method. Ten subjects had the A1/A2 genotype, eleven subjects had the A2/A2 genotype, and no subject had the A1/A1 genotype. The domain size, including the thalamus and basal ganglia that were inside each side of the putamens, did not differ between the three groups (the A1/A2-group, the A2/A2-group, and the young healthy person group). In the comparison based on this domain, the temporal lobe tended to narrow in the A2/A2-group compared to the A1/A2-group (P = .06). The other domain (cerebrum, corpus callosum, etc.) showed no difference between the A1/A2-group and the A2/A2-group. It is suggested that in methamphetamine psychosis the TaqI A polymorphism not only regulates prolongation of psychosis symptoms but also influences the form of the temporal lobe.

Adult↗

PubMed2003

Congenic C57BL/6 mu opiate receptor (MOR) knockout mice: baseline and opiate effects.

Homozygous mu-opioid receptor (MOR) knockout (KO) mice developed on a chimeric C57B6/129SV background lack morphine-induced antinociception, locomotion and reward. Therefore it appears that MOR largely mediates these morphine actions. However, one factor that could affect the extent of knockout deficits in morphine-induced behavior is the genetic background against which the gene deletion is expressed. To examine the effect of genetic background chimeric C57B6/129SV MOR knockout mice from the 15th generation of those developed in our laboratory were backcrossed for 10 successive generations with C57BL/6 mice, a strain which is more sensitive to many of the properties of morphine, to produce congenic MOR (con-MOR) KO mice. Heterozygote conMOR KO mice display attenuated morphine locomotion and reduced morphine analgesia compared to wild-type mice. Homozygote con-MOR KO mice display baseline hyperalgesia, no morphine place preference, no morphine analgesia and no morphine locomotion. These results are not qualitatively different from those observed in the MOR KO strain with a chimeric C57B6/129SV background, and suggest that although the strain has separate influences on these functions, it does not substantially interact with deletion of the mu opiate receptor gene.

Analgesia↗

PubMed2003

Nine- or fewer repeat alleles in VNTR polymorphism of the dopamine transporter gene is a strong risk factor for prolonged methamphetamine psychosis.

Susceptibility to drug dependence and drug-induced psychoses is influenced not only by the pharmacological effects of the drug but also by the genetic factors of the individual. To clarify the latter, we investigated the association between methamphetamine (METH) dependence/psychosis and the hDAT1 gene (SLC6A3) encoding the dopamine transporter, which is the primary site of METH activity in the brain. Four exonic polymorphisms of the hDAT1 gene, 242C/T (exon 2), 1342A/G (exon 9), 2319G/A (3'UTR), and VNTR (3'UTR) were examined. Although there was no significant difference in genotypic and allelic distribution of the four polymorphisms between all METH dependence/psychosis patients (N=124) and controls (N=160), the patients with METH psychosis lasting for 1 month or more after discontinuance of METH consumption showed a significant excess of nine- or fewer repeat alleles of the VNTR in 3'UTR of the hDAT1 gene (P=0.0054, OR=4.24, 95% CI=2.46-7.31). The present study demonstrated that the presence of nine- or fewer repeat alleles of hDAT1 is a strong risk factor for a worse prognosis of METH psychosis.

Adult↗

PubMed2003

Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders.

Current evidence indicates that virtually all neuropsychiatric disorders, like many other common medical disorders, are genetically complex, with combined influences from multiple interacting genes, as well as from the environment. However, additive or epistatic gene interactions have proved quite difficult to detect and evaluate in human studies. Mouse phenotypes, including behaviors and drug responses, can provide relevant models for human disorders. Studies of gene-gene interactions in mice could thus help efforts to understand the molecular genetic bases of complex human disorders. The serotonin transporter (SERT, 5-HTT, SLC6A4) provides a relevant model for studying such interactions for several reasons: human variants in SERT have been associated with several neuropsychiatric and other medical disorders and quantitative traits; SERT blockers are effective treatments for a number of neuropsychiatric disorders; there is a good initial understanding of the phenotypic features of heterozygous and homozygous SERT knockout mice; and there is an expanding understanding of the interactions between variations in SERT expression and variations in the expression of a number of other genes of interest for neuropsychiatry and neuropharmacology. This paper provides examples of experimentally-obtained interactions between quantitative variations in SERT gene expression and variations in the expression of five other mouse genes: DAT, NET, MAOA, 5-HT(1B) and BDNF. In humans, all six of these genes possess polymorphisms that have been independently investigated as candidates for neuropsychiatric and other disorders in a total of > 500 reports. In the experimental studies in mice reviewed here, gene-gene interactions resulted in either synergistic, antagonistic (including 'rescue' or 'complementation') or more complex, quantitative alterations. These were identified in comparisons of the behavioral, physiological and neurochemical phenotypes of wildtype mice vs. mice with single allele or single gene targeted disruptions and mice with partial or complete disruptions of multiple genes. Several of the descriptive phenotypes could be best understood on the basis of intermediate, quantitative alterations such as brain serotonin differences. We discuss the ways in which these interactions could provide models for studies of gene-gene interactions in complex human neuropsychiatric and other disorders to which SERT may contribute, including developmental disorders, obesity, polysubstance abuse and others.

Animals↗

PubMed2002

Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) knockout mice.

Several lines of evidence suggest that monoaminergic systems, especially dopaminergic and serotoninergic systems, modulate ethanol consumption. Humans display significant differences in expression of the vesicular and plasma membrane monoamine transporters important for monoaminergic functions, including the vesicular monoamine transporter (VMAT2, SLC18A2) and dopamine transporter (DAT, SLC6A3). In addition, many ethanol effects differ by sex in both humans and animal models. Therefore, ethanol consumption and preference were compared in male and female wild-type mice, and knockout (KO) mice with deletions of genes for DAT and VMAT2. Voluntary ethanol (2-32% v/v) and water consumption were compared in two-bottle preference tests in wild-type (+/+) vs heterozygous VMAT2 KO mice (+/-) and in wild-type (+/+) vs heterozygous (+/-) or homozygous (-/-) DAT KO mice. Deletions of either the DAT or VMAT2 genes increased ethanol consumption in male KO mice, although these effects were highly dependent on ethanol concentration, while female DAT KO mice had higher ethanol preferences. Thus, lifetime reductions in the expression of either DAT or VMAT2 increase ethanol consumption, dependent on sex.

Alcohol Drinking↗

PubMed2002

Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions.

Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine, serotonin and norepinephrine, producing subjective effects in humans that are both euphoric/rewarding and also fearful, jittery and aversive. Mice with gene knockouts of each of these transporters display cocaine reward, manifest by cocaine place preferences that are at least as great as wildtype values. Norepinephrine and serotonin receptor knockouts even display enhanced cocaine reward. One explanation for these observations could be that cocaine produces aversive or anhedonic effects by serotonin or norepinephrine receptor blockade in wildtype mice that are removed in serotonin or norepinephrine receptor knockouts, increasing net cocaine reward. Adaptations to removing one transporter could also change the rewarding valence of blocking the remaining transporters. To test these ideas, drugs that block serotonin transporter (fluoxetine), norepinephrine transporter (nisoxetine) or all three transporters (cocaine) were examined in single- or multiple-transporter knockout mice. Fluoxetine and nisoxetine acquire rewarding properties in several knockouts that are not observed in wildtype mice. Adding serotonin transporter knockout to norepinephrine transporter knockouts dramatically potentiates cocaine reward. These and previous data provide evidence that serotonin and norepinephrine transporter blockade can contribute to the net rewarding valence of cocaine. They identify neuroadaptations that may help to explain the retention of cocaine reward by dopamine and serotonin transporter knockout mice. They are consistent with emerging hypotheses that actions at the three primary brain molecular targets for cocaine each provide distinct contributions to cocaine reward and cocaine aversion in wildtype mice, and that this balance changes in mice that develop without dopamine, norepinephrine or serotonin transporters.

Animals↗

PubMed2002

Antagonistic property of buprenorphine for putative epsilon-opioid receptor-mediated G-protein activation by beta-endorphin in pons/medulla of the mu-opioid receptor knockout mouse.

beta-Endorphin is a non-selective opioid peptide which binds mu-, delta- and putative epsilon (beta-endorphin-sensitive non-mu-, non-delta- and non-kappa(1)-)-opioid receptors. We have previously reported that beta-endorphin-produced G-protein activation is mediated by the stimulation of both mu- and putative epsilon-opioid receptors. The present study was designed to further characterize this putative epsilon-opioid receptor-mediated G-protein activation in the pons/medulla membrane obtained from mice lacking mu-opioid receptor, using a guanosine-5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS)-binding assay. beta-Endorphin and the mu-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) increased the [(35)S]GTPgammaS binding in a concentration-dependent manner (0.001-10 microM), and at 10 microM beta-endorphin and DAMGO produced approximately 250 and 120% increases of [(35)S]GTPgammaS binding in the pons/medulla membrane obtained from wild-type mice, respectively. In the pons/medulla membrane obtained from mu-opioid receptor knockout mice, beta-endorphin-stimulated [(35)S]GTPgammaS binding was only partially attenuated and a more than 100% increase by 10 microM beta-endorphin still remained, while DAMGO failed to produce any increase in [(35)S]GTPgammaS binding. The residual increase in [(35)S]GTPgammaS binding by 10 microM beta-endorphin in mu-opioid receptor knockout mice was partially but significantly attenuated by the putative epsilon-opioid receptor partial agonist beta-endorphin (1-27), but not by the delta-opioid receptor antagonist naltrindole or the kappa(1)-receptor antagonist norbinaltorphimine. Furthermore, buprenorphine significantly attenuated the residual increase in [(35)S]GTPgammaS binding by 10 microM beta-endorphin in mu-opioid receptor knockout mice. The present results indicate that beta-endorphin activates G-protein by stimulation of putative epsilon-opioid receptors in the condition lacking the mu-opioid receptor, and buprenorphine acts as an antagonist for putative epsilon-opioid receptors in this condition.

Animals↗

PubMed2002

Cocaine, reward, movement and monoamine transporters.

Recent evidence enriches our understanding of the molecular sites of action of cocaine reward and locomotor stimulation. Dopamine transporter blockade by cocaine appears a sufficient explanation for cocaine-induced locomotion. Variation in DAT appears to cause differences in locomotion without drug stimulation. However, previously-held views that DAT blockade was the sole site for cocaine reward have been replaced by a richer picture of multitransporter involvement with the rewarding and aversive actions of cocaine. These new insights, derived from studies of knockout mice with simultaneous deletions and/or blockade of multiple transporters, provide a novel model for the rewarding action of this heavily-abused substance and implicate multiple monoamine systems in cocaine's hedonic activities.

Animals↗

PubMed2001

Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release.

Thalamocortical neurons innervating the barrel cortex in neonatal rodents transiently store serotonin (5-HT) in synaptic vesicles by expressing the plasma membrane serotonin transporter (5-HTT) and the vesicular monoamine transporter (VMAT2). 5-HTT knock-out (ko) mice reveal a nearly complete absence of 5-HT in the cerebral cortex by immunohistochemistry, and of barrels, both at P7 and adulthood. Quantitative electron microscopy reveals that 5-HTT ko affects neither the density of synapses nor the length of synaptic contacts in layer IV. VMAT2 ko mice, completely lacking activity-dependent vesicular release of monoamines including 5-HT, also show a complete lack of 5-HT in the cortex but display largely normal barrel fields, despite sometimes markedly reduced postnatal growth. Transient 5-HTT expression is thus required for barrel pattern formation, whereas activity-dependent vesicular 5-HT release is not.

Aging↗