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Ichiro Sora

Publications and source records attributed to Ichiro Sora.

At least 55 records · Page 3Linked to original sources
PubMed2004

Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters.

Cocaine conditioned place preference (CPP) is intact in dopamine transporter (DAT) knockout (KO) mice and enhanced in serotonin transporter (SERT) KO mice. However, cocaine CPP is eliminated in double-KO mice with no DAT and either no or one SERT gene copy. To help determine mechanisms underlying these effects, we now report examination of baselines and drug-induced changes of extracellular dopamine (DAex) and serotonin (5-HT(ex)) levels in microdialysates from nucleus accumbens (NAc), caudate putamen (CPu), and prefrontal cortex (PFc) of wild-type, homozygous DAT- or SERT-KO and heterozygous or homozygous DAT/SERT double-KO mice, which are differentially rewarded by cocaine. Cocaine fails to increase DAex in NAc of DAT-KO mice. By contrast, systemic cocaine enhances DAex in both CPu and PFc of DAT-KO mice though local cocaine fails to affect DAex in CPu. Adding SERT to DAT deletion attenuates the cocaine-induced DAex increases found in CPu, but not those found in PFc. The selective SERT blocker fluoxetine increases DAex in CPu of DAT-KO mice, while cocaine and the selective DAT blocker GBR12909 increase 5-HT(ex) in CPu of SERT-KO mice. These data provide evidence that (a) cocaine increases DAex in PFc independently of DAT and that (b), in the absence of SERT, CPu levels of 5-HT(ex) can be increased by blocking DAT. Cocaine-induced alterations in CPu DA levels in DAT-, SERT-, and DAT/SERT double-KO mice appear to provide better correlations with cocaine CPP than cocaine-induced DA level alterations in NAc or PFc.

Animals↗
PubMed2004

Nerve injury induces a tonic bilateral mu-opioid receptor-mediated inhibitory effect on mechanical allodynia in mice.

BACKGROUND: Mice lacking the mu-opioid receptor gene have been used to characterize the role of mu-opioid receptors in nociception and the analgesic actions of opioid agonists. In this study, the authors determined the role of mu-opioid receptors in neuropathic pain behaviors and the effectiveness of mu- and kappa-opioid receptor agonists on this behavior in mice. METHODS: The authors studied the behavioral responses of mu-opioid receptor knockout and wild-type mice to thermal and mechanical stimuli before and after neuropathic pain induced by unilateral ligation and section of the L5 spinal nerve. Response to mechanical stimuli was evaluated by determining the frequency of hind paw withdrawal to repetitive stimulation using a series of von Frey monofilaments. Thermal hyperalgesia was assessed by determining the paw withdrawal latencies to radiant heat and frequency of hind paw withdrawal to cooling stimuli. The effects of systemic morphine, the kappa-opioid agonist U50488H, and naloxone on responses to mechanical and thermal stimuli were also studied in spinal nerve-injured mice. RESULTS: After spinal nerve injury, wild-type mice developed increased responsiveness to mechanical, heat, and cooling stimuli ipsilateral to nerve injury. mu-Opioid receptor knockout mice not only had more prominent mechanical allodynia in the nerve-injured paw, but also expressed contralateral allodynia to mechanical stimuli. Hyperalgesia to thermal stimuli was similar between mu-opioid knockout and wild-type animals. Morphine decreased mechanical allodynia dose dependently (3-30 mg/kg subcutaneous) in wild-type mice--an effect that was attenuated in the heterozygous mice and absent in the homozygous mu-opioid knockout mice. The kappa-opioid agonist U50488H (3-10 mg/kg subcutaneous) attenuated mechanical allodynia in wild-type, heterozygous, and homozygous mu-opioid mice. Naloxone in wild-type mice resulted in enhanced ipsilateral and contralateral allodynia to mechanical stimuli that resembled the pain behavior observed in mu-opioid receptor knockout mice. CONCLUSIONS: The authors' observations indicate that (1) unilateral nerve injury induces a bilateral tonic activation of endogenous mu-opioid receptor-mediated inhibition that attenuates mechanical allodynia but not thermal hyperalgesia, (2) both mu- and kappa-opioid agonists attenuate neuropathic pain in mice, and (3) the antihyperalgesic actions of morphine are mediated primarily via mu-opioid receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2004

A possible genetic mechanism underlying individual and interstrain differences in opioid actions: focus on the mu opioid receptor gene.

Individual differences in responses to opioids limit effective pain treatment with these drugs. Identifying the mechanism could help to improve the analgesic effects of them. Since the molecular cloning of the mu opioid receptor (muOR) gene, substantial advances in opioid research have been made, including the discoveries that muOR plays a mandatory role in the analgesic effects of opioids and that the sequence of the muOR gene varies from one individual to another. It is conceivable that the differences in the muOR gene cause individual differences in opioid actions. The present review summarizes the recent advances made in research on human and mouse muOR genes and proposes that the variances in the 3' untranslated region (39-UTR) of the muOR gene might participate in the variability of the opioid response.

Animals↗
PubMed2004

Molecular mechanisms underlying the rewarding effects of cocaine.

The initially surprising observation that cocaine retains its rewarding effects in dopamine transporter (DAT) knockout (KO) mice led our laboratory to examine the effects of deletion of other monoaminergic genes on cocaine reward. Our initial approach to this problem was to combine DAT KO mice with serotonin transporter (SERT) KO mice to make combined DAT/SERT KO mice. The combination of these knockouts eliminates cocaine reward as assessed in the conditioned place preference (CPP) paradigm. We have also identified evidence that, in the absence of DAT, there is greater participation in cocaine reward by serotonin (SERT) and norepinephrine (NET) transporters. Both NET and SERT blockers (nisoxetine and fluoxetine) produced significant CPPs in DAT KO mice, but not in wild-type (WT) mice. The striking elimination of cocaine CPP in combined DAT/SERT KO mice contrasts with effects that we have identified in combined NET/SERT knockout mice, which display increases in cocaine reward, and with recent reports that suggest that DAT/NET combined KOs retain substantial cocaine CPP. Overall, these studies indicate important requirements for several monoaminergic system genes to fully explain cocaine reward, in particular those expressed by dopamine and serotonin systems.

Animals↗
PubMed2004

Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain.

Methamphetamine (MAP), the most frequently abused substance in Japan, causes severe drug dependence and psychosis, similar to schizophrenia. It is suggested that long-term alterations in gene expression is related to MAP-induced brain dysfunction, including dependence and psychosis. DNA (cytosine-5) methyltransferase (Dnmt), a methylating enzyme of cytosine residues on CpG-dinucleotides, plays an important role in X chromosome inactivation, genomic imprinting, and gene expression. Reelin is an extracellular matrix protein secreted by GABAergic interneurons. Heterozygous reeler mice that exhibit a 50% downregulation of reelin expression replicate the dendritic spine and GABAergic defects described in schizophrenia. DNA methylation plays an important role in the epigenetic modification of reelin expression. We previously found that MAP could alter expression of Dnmt1 mRNA in the rat brain. In this study, we examined the brain mRNA for Dnmt2 and reelin in MAP-treated Wistar rats. Acute MAP (4 mg/kg) treatment significantly decreased Dnmt2 mRNA by 27% to 39% in hippocampus dentate gyrus, CA1, and CA3 24 h after treatment, and significantly decreased reelin mRNA by 28% in frontal cortex 3 h after treatment. These results suggest that (1) MAP can alter DNA methylation as well as expression of genes in these brain regions, and (2) decrease in reelin mRNA in the frontal cortex is similar to heterozygous reeler mice, which might be related to schizophrenia-like psychotic symptoms of MAP psychosis.

Animals↗
PubMed2004

Food-reinforced operant behavior in dopamine transporter knockout mice: enhanced resistance to extinction.

Dopamine (DA) plays roles in circuits that are important for brain reward and in striatal brain regions that are important for certain types of habit learning. These processes in wildtype, heterozygous, and homozygous dopamine transporter knockout (DAT-KO) mice, which were mildly food deprived and allowed to make nose-poke responses for food reinforcement, were studied. The mice were given 20-min sessions of daily (a) baseline exposure to the operant chambers, (b) acquisition of nose-poke responses in which responses were reinforced under a fixed ratio (FR5) schedule, (c) a progressive ratio schedule in which the number of responses required to obtain food was gradually increased, and (d) extinction of responses in which nose pokes were not followed by food. Neither heterozygous nor homozygous DAT-KO mice differed from their wildtype litter mates in the number of nose pokes displayed during baseline exposures to the chambers, the number of sessions required for acquisition, the number of responses under the FR5 schedule, or the number of responses under the progressive ratio schedule. Interestingly, however, in the five extinction sessions in which food was no longer delivered by nose poking, homozygous DAT-KO mice exerted significantly more responses than mice of either of the other two genotypes. These lines of evidence suggest a greater resistance of DAT-KO mice to the elimination of the response and support roles of dopaminergic systems in habit memory.

Animals↗
PubMed2004

Gene polymorphisms of the mu opioid receptor in methamphetamine abusers.

In drug addiction, the opioid system is thought to mediate motivational effects through dopamine-independent mechanisms. We have investigated associations of the mu-opioid receptor gene (OPRM) variations with methamphetamine (MAP) dependence/psychosis. The allelic frequency of A118G (Asn40Asp) in exon 1 of ORPM was 45.3% in our control subjects, but only 7.5-25.8% in the Caucasian or African-American population of previous studies. We have identified several novel polymorphisms in intron 1 and the 5' untranslated region (5'UTR) of OPRM. Polymorphisms in the functionally relevant 5' regulatory region of OPRM were different in our Japanese population from Caucasian or African-American populations. No significant differences between controls and MAP abusers were found in either genotype or allele frequency at any single nucleotide polymorphism (SNP) or (AC)n dinucleotide repeat in intron 1. A subdivision of our MAP group revealed that A118G of OPRM shows a significant association with MAP psychosis having latency less than three years. Further analysis should be capable of identifying associations between the OPRM variations and MAP dependence/psychosis.

Adult↗
PubMed2004

Study of association between alpha-synuclein gene polymorphism and methamphetamine psychosis/dependence.

Methamphetamine (MAP) dissipates proton gradients across the membranes of synaptic vesicles, enhances cytoplasmic dopamine (DA) concentrations, and causes calcium-independent, nonvesicular DA release into synapses. MAP is taken into the cytosol by the dopamine transporter (DAT) on the synaptic terminals of DA neurons, and endogenous DA is concurrently released through the transporter by carrier exchange mechanisms, resulting in a robust increase in DA concentration in the synaptic clefts. The enhanced DA release through DAT by MAP is the main mechanism for the reinforcing effects of MAP. The complexes of alpha-synuclein and DAT facilitate membrane clustering of the DAT, thereby accelerating DA uptake in vitro. alpha-Synuclein has been shown to be overexpressed in the midbrain DA neurons of chronic cocaine abusers. The present study was performed to study the association between the alpha-synuclein gene polymorphisms and MAP psychosis/dependence in Japanese population. Since the T10A7 polymorphic site at the 5' end of the noncoding exon 1' in the alpha-synuclein gene is highly polymorphic, we analyzed the noncoding exon 1' and intron 1, including this polymorphic site by sequencing. We confirmed four single nucleotide polymorphisms (SNPs) within 1.38 kbp of the T10A7 polymorphic site. No significant difference was found in genotype or allele frequencies in the T10A7 polymorphic site between MAP psychotic/dependent and control subjects. We found significant association between three SNPs in the vicinity of this polymorphic site in intron 1 and MAP psychosis/dependence in female subjects, but not in males. These results suggest an association of the alpha-synuclein gene polymorphisms with MAP psychosis/dependence in our female subjects. Further analyses are necessary to clarify the gender difference, by using a larger sample size and/or different ethnic groups, as well as functional variations in the alpha-synuclein gene.

Adult↗
PubMed2003

Association between a novel polymorphism in the promoter region of the neuropeptide Y gene and schizophrenia in humans.

Hypoactivity of neuropeptide Y (NPY) is thought to be involved in the pathophysiology of schizophrenia, because post-mortem brain studies revealed a decrease of the NPY in schizophrenia, and antipsychotic treatments increase the NPY in animal brains and in cerebrospinal fluid of patients. We performed genetic analysis of the NPY gene in schizophrenia. Mutation screening of the gene detected nine single nucleotide polymorphisms, of which we typed a -485C>T variation from potential functional relevance. The -485T allele was overly represented in the disease group (P=0.0043). An in vitro promoter assay revealed that a C to T change at nt -485 significantly reduced transcriptional activity. These results suggest that the -485T allele in NPY may confer susceptibility to schizophrenia by decreasing the neuropeptide in brains.

Genetic Predisposition to Disease↗
PubMed2003

Caspase-independent cell death by low concentrations of nitric oxide in PC12 cells: involvement of cytochrome C oxidase inhibition and the production of reactive oxygen species in mitochondria.

We reported previously that low levels of nitric oxide (NO) induced cell death with properties of apoptosis, including chromatin fragmentation and condensation in undifferentiated PC12 pheochromocytoma cells. The present study demonstrates that cytotoxicity of low concentrations of NO is mediated by inhibition of mitochondrial cytochrome c oxidase and generation of reactive oxygen species (ROS). An NO donor, (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3) induced cell death even at low concentrations (10-100 microM), whereas peroxynitrite and a peroxynitrite generator, 3-(4-morpholinyl)-sydnonimine (SIN-1), did not have a significant effect on cell viability up to a concentration of 0.5 mM. The NOR3-induced cell death was unaffected by pretreatment with superoxide dismutase (SOD) or its mimetic peroxynitrite scavenger, manganese(III) tetrakis(benzoic acid)porphyrin chloride (Mn-TBAP), or with uric acid. These findings indicate that peroxynitrite does not contribute to this cell death. Furthermore, neither the release of cytochrome c from mitochondrial membranes, the cleavage of poly-ADP ribose polymerase (PARP), nor the activation of caspase-3-like activities was observed. Inhibitors of PARP, benzamide, and aminobenzamide, had no effect on the NOR3-induced cell death. In addition, pretreatment with general or selective caspase inhibitors, benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk), N-acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO), and benzyloxycarbonyl-Asp-2,6-dichlorobenzoyloxymethylketone (Z-Asp-Ch(2)-DCB) did not prevent NOR3-induced cell death. Taken together, these findings suggest that cell death induced by NOR3 occurs by a caspase-independent mechanism. In contrast, we found an early increase in mitochondrial H(2)O(2) production during NOR3 exposure using the fluorescent dye 2',7'-dichlorofluorescin-diacetate (DCFH-DA) and dihydrorohdamine123 (DHR123), and these events were accompanied by strong inhibition of cytochrome c oxidase activity in the cells. Furthermore, we observed that several antioxidants, such as ascorbate, glutathione (GSH), cysteine, tetrahydrobiopterin, and dithiothreitol (DTT), all effectively prevented the NOR3-induced cell death. NOR3 treatment decreased the level of total intracellular GSH, but did not affect the activities of antioxidant enzymes SOD, GSH-peroxidase (GPX), and catalase. These results suggest that cell death induced at physiologically low concentrations of NO is mediated by ROS production in mitochondria, most likely resulting from the inhibition of cytochrome c oxidase, with ROS acting as an initiator of caspase-independent cell death.

Animals↗
PubMed2003

Overexpression of V-1 prevents nitric oxide-induced cell death: involvement of enhanced tetrahydrobiopterin biosynthesis.

Previously we reported that the synthesis of catecholamines, dopamine, and noradrenaline was enhanced by overexpression of V-1 protein, a neuronal protein active in the initial stage of development of the rat cerebellum, in the neuronal cell line PC12D, a model of dopamine cells (Yamakuni et al. [1998] J. Biol. Chem. 273:27051-27054). To investigate the physiological role of this protein, we examined the effect of V-1 overexpression on cell toxicity induced by nitric oxide (NO) used at low concentrations. Two clones of PC12D cells overexpressing V-1, transfectants termed V1-46 and V1-69, were significantly more resistant to NOR3 (an NO donor) but not to etoposide (an inhibitor of topoisomerase II)-induced apoptotic cell death than the control cells (termed C-7 and C-9) that had been transfected with the vector alone. The addition of L-DOPA, dopamine, or noradrenaline to the medium did not abolish NOR3-induced cell death in PC12D cells. Moreover, pretreatment of V1-46 and V1-69 cells with L-alpha-methyl-p-tyrosine (alpha-MPT), an inhibitor of tyrosine hydroxylase, to inhibit catecholamine biosynthesis did not affect the resistance to NO toxicity. These results indicate that the catecholamine levels increased by V-1 overexpression did not produce the protection against NOR3-induced toxicity. We further showed that overexpression of V-1 enhanced the synthesis of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)). In addition, pretreatment with BH(4) or with sepiapterin, which is converted to BH(4) intracellularly, significantly protected PC12D cells in a dose-dependent manner. The increased BH(4) synthesis by V-1 overexpression was dose dependently inhibited by pretreatment with diaminohydroxypyrimidine (DAHP), an inhibitor of GTP-cyclohydrolase I, which is the rate-limiting enzyme for the biosynthesis of BH(4), concomitantly with the loss of protective effect afforded by V-1 overexpression. Furthermore, the addition of BH(4) or sepiapterin to DAHP-pretreated V146 and V1-69 cells restored cell viability. Taken together, these results indicate that V1 protein plays an important role in protection against cell death induced by NO at low levels by promoting the synthesis of BH(4). Moreover, these findings suggest the up-regulation of V1 expression as a possible therapeutic target for protection against the insult of NO-induced oxidative stress.

Animals↗
PubMed2003

Lack of mu-opioid receptor-mediated G-protein activation in the spinal cord of mice lacking Exon 1 or Exons 2 and 3 of the MOR-1 gene.

The G-protein activation induced by mu-opioid receptor agonists was determined in spinal cord membranes from two types of mu-opioid receptor knockout mice: mice with a disruption of exon 1 (MOR (Exon 1)-KO) or exons 2 and 3 (MOR (Exons 2 and 3)-KO) of the mu-opioid receptor gene. The G-protein activation induced by the opioid agonists was measured by monitoring the increases of guanosine-5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTP gamma S) binding. The mu-opioid receptor agonists (D-Ala(2),N-MePhe (4),Gly-ol(5)]enkephalin, endomorphin-1, endomorphin-2, morphine, morphine-6 beta-glucuronide, and fentanyl produced concentration-dependent increases of [(35)S]GTP gamma S binding to spinal cord membranes in wild-type mice, but not in MOR (Exon 1)-KO mice or MOR (Exons 2 and 3)-KO mice. On the other hand, the delta-opioid receptor agonist [D-Pen (2,5)]enkephalin, the kappa-opioid receptor agonist (-)U50,488H, or the ORL1-receptor agonist nociception increased [(35)S]GTP gamma S binding in the spinal cord membranes from both MOR (Exon 1)-KO mice and MOR (Exons 2 and 3)-KO mice to the same extent as in the corresponding wild-type mice. The results provide further information about the important roles of the sequences encoded within exon 1 and exons 2 and 3 of mu-opioid receptor gene for the activation of G-proteins by mu-opioid receptor agonists in the mouse spinal cord.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2002

Effects of acute "binge" cocaine on preprodynorphin, preproenkephalin, proopiomelanocortin, and corticotropin-releasing hormone receptor mRNA levels in the striatum and hypothalamic-pituitary-adrenal axis of mu-opioid receptor knockout mice.

Cocaine administration increases activity at dopamine receptors, increases preprodynorphin (ppDyn) gene expression in the caudate-putamen (CPu), and activates the stress responsive hypothalamic-pituitary-adrenal (HPA) axis. To examine the hypothesis that mu-opioid receptors (MOR) may play roles in these cocaine effects, we tested the effects of acute "binge" pattern cocaine administration in mice with targeted disruption of the MOR gene. Wild-type (+/+) and homozygous MOR-deficient (-/-) mice received three injections of 15 mg/kg cocaine at 1-h intervals. Mice were sacrificed 30 min after the last injection and mRNAs for ppDyn and preproenkephalin (ppEnk) in the CPu and nucleus accumbens (NAc), and for type I corticotropin-releasing hormone receptor (CRH(1) receptor) and pro-opiomelanocortin (POMC) in the hypothalamus and pituitary, were measured by solution hybridization RNase protection assays. Cocaine elevated ppDyn mRNA in the CPu, but not NAc, of both the MOR -/- and wild-type mice. ppEnk mRNA in the CPu, but not NAc, was lower in MOR -/- mice than in wild-type mice following cocaine administration. Hypothalamic CRH(1) receptor and POMC mRNAs were expressed at similar levels in untreated and in cocaine-treated mice of each genotype. However, there were lower basal levels of CRH(1) receptor mRNA in the anterior pituitary of the MOR -/- mice than in wild-type mice and the MOR -/- mice failed to show the cocaine-induced decreases in CRH(1) receptor mRNA found in the wild-type mice. Cocaine activated the HPA axis similarly in MOR -/- and wild-type mice, as reflected in similar increases in plasma corticosterone levels in both genotypes. These results support a specific role for MORs in acute cocaine effects on striatal ppEnk gene expression and fail to support critical roles for these receptors in acute cocaine's effects on either ppDyn gene expression or HPA activation. MOR -/- mice are useful models for studying cocaine effects on ppEnk gene expression that could aid interpretation of the similar postmortem phenomena found in human cocaine addicts.

Animals↗