Yasushi Kajii

Tokyo Medical and Dental University, Edo, Tokyo, Japan

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Publications (17)56.39 Total impact

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    ABSTRACT: The psychotomimetic effects of stimulant drugs including amphetamines and cocaine are known to change during the postnatal development in humans and experimental animals. To obtain an insight into the molecular basis of the onset of stimulant-induced psychosis, we have explored the gene transcripts that differentially respond to methamphetamine (MAP) in the developing rat brains using a differential cloning technique, the RNA arbitrarily-primed PCR. We identified from the rat neocortex a novel and developmentally regulated MAP-inducible gene mrt3 (MAP responsive transcript 3) that is transcribed to a presumable non-coding RNA of 3.8 kb and is located on the reverse strand of the F-box/LRR-repeat protein 17-like gene mapped on the rat chromosome Xq12. The mrt3 mRNAs are predominantly expressed in the brain and lung. Acute MAP injection upregulated the mrt3 expression in the neocortex at postnatal day 50, but not days 8, 15 and 23, in a D1 receptor antagonist-sensitive manner. This upregulation was mimicked by another stimulant, cocaine, whereas pentobarbital and D1 antagonist failed to alter the mrt3 expression. Moreover, repeated treatment with MAP for 5 days inhibited the ability of the challenge dose of MAP or cocaine to increase the neocortical mrt3 expression without affecting the basal mrt3 mRNA levels on day 14 of withdrawal. These late-developing, cocaine-cross reactive, D1 antagonist-sensitive and long-term regulations of mrt3 by MAP are similar to those of stimulant-induced behavioral sensitization, a model of the onset and relapse of stimulant-induced psychosis and schizophrenia, and therefore may be associated with the pathophysiology of the model.
    No preview · Article · Oct 2014 · European Neuropsychopharmacology
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    ABSTRACT: A growing body of evidence suggests the involvement of inflammatory processes in the pathophysiology of schizophrenia. Four to eight-week exposure to cuprizone, a copper chelator, causes robust demyelination and has been used to build a model for multiple sclerosis. In contrast, we report here the effects of one-week cuprizone exposure in mice. This short-term cuprizone exposure elicits behavioral changes that include augmented responsiveness to methamphetamine and phencyclidine, as well as impaired working memory. The cellular effects of one-week cuprizone exposure differ substantially from the longer-term exposure; perturbation of astrocytes and microglia is induced without any sign of demyelination. Furthermore, the proinflammatory cytokine interleukin-6 was significantly up-regulated in glial fibrillary acidic protein (GFAP)-positive cells. We propose that this cuprizone short-term exposure may offer a model to study some aspects of biology relevant to schizophrenia and related conditions.
    No preview · Article · Jul 2013 · Neurobiology of Disease

  • No preview · Article · Apr 2013 · Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology
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    ABSTRACT: In an in vivo dialysis experiment, the intra-medial frontal cortex infusion of a system A and Asc-1 transporter inhibitor, S-methyl-L-cysteine, caused a concentration-dependent increase in the dialysate contents of an endogenous coagonist for the N-methyl-D-aspartate (NMDA) type glutamate receptor, D-serine, in the cortical portion. These results suggest that these neutral amino acid transporters could control the extracellular D-serine signaling in the brain and be a target for the development of a novel threapy for neuropsychiatric disorders with an NMDA receptor dysfunction.
    No preview · Article · Feb 2013 · Amino Acids
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    ABSTRACT: Using the RNA arbitrarily-primed PCR and the competitive RT-PCR, we have isolated the neocortical transcripts that are upregulated and unchanged in the adult and infant rats, respectively, after a systemic injection of an N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP), and found them identical to the synapse-associated protein-97 (SAP97) gene mRNAs. The upregulation of the SAP97 transcripts in the adult neocortex after the acute PCP injection was mimicked by another NMDA antagonist, dizocilpine, but not by the indirect dopamine agonists, methamphetamine and cocaine, a selective D1 receptor antagonist SCH23390, a D2 receptor-preferring antagonist haloperidol and a GABAergic anesthetic pentobarbital. Moreover, the pretreatment with a typical antipsychotic haloperidol failed to antagonize the increased neocortical SAP97 gene expression by PCP. These findings suggest that SAP97 might be involved in the molecular basis of the development-dependent onset of the non-dopaminergic symptoms seen in schizophrenia and the schizophrenia-like psychosis induced by NMDA receptor blocking.
    No preview · Article · Oct 2009 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    ABSTRACT: Methamphetamine is a potent and indirect dopaminergic agonist which can cause chronic brain dysfunctions including drug abuse, drug dependence and drug-induced psychosis. Methamphetamine is known to trigger molecular mechanisms involved in associative learning and memory, and thereby alter patterns of synaptic connectivity. The persistent risk of relapse in methamphetamine abuse, dependence and psychosis may be caused by such alterations in synaptic connectivity. EphA5 receptors constitute large families of tyrosine kinase receptor and are expressed almost exclusively in the nervous system, especially in the limbic structures. Recent studies suggest EphA5 to be important in the topographic projection, development, and plasticity of limbic structures, and to be involved in dopaminergic neurotransmission. We used in situ hybridization to examine whether methamphetamine alters EphA5 mRNA expression in the brains of adult male Wister rats. EphA5 mRNA was widely distributed in the medial frontal cortex, cingulate cortex, piriform cortex, hippocampus, habenular nucleus and amygdala. Compared to baseline expression at 0h, EphA5 mRNA was significantly decreased (by 20%) in the medial frontal cortex at 24h, significantly increased (by 30%) in the amygdala at 9 and 24h, significantly but transiently decreased (by 30%) in the habenular nucleus at 1h after a single injection of methamphetamine. Methamphetamine did not change EphA5 mRNA expression in the cingulate cortex, piriform cortex or hippocampus. Our results that methamphetamine altered EphA5 mRNA expression in rat brain suggest methamphetamine could affect patterns of synaptic connectivity, which might be responsible for methamphetamine-induced chronic brain dysfunctions.
    No preview · Article · Oct 2007 · Neuroscience Letters
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    ABSTRACT: This study examined the effects of the selective 5-HT1A receptor agonist osemozotan on repeated methamphetamine (METH)-induced behavioral sensitization and single METH-induced locomotor stimulant effect in mice, and then the neurochemical mechanisms using in vivo microdialysis. Repeated administration of METH for 7 days enhanced METH challenge-induced locomotor activity, and this sensitization was observed even after its withdrawal for 7-14 days. Administration of osemozotan to METH-sensitized mice inhibited the maintenance of behavioral sensitization. This effect was blocked by a low dose of WAY100635, a selective 5-HT1A receptor antagonist. A METH challenge increased the extracellular levels of dopamine (DA), 5-HT, and noradrenaline in the prefrontal cortex, but only the increase in 5-HT release was enhanced by repeated METH administration. This augmented response of 5-HT release was attenuated by osemozotan in a WAY100635-sensitive way. A single administration of osemozotan to drug naïve mice inhibited METH-induced locomotor stimulant effect and reduced METH-induced increase in prefrontal 5-HT, but not DA, release. These results suggest that prefrontal 5-HT release is involved at least partly in the effects of osemozotan on single and repeated METH-induced behavioral effects in mice, and imply that the 5-HT1A receptors may have a potential therapeutic value in the remission of schizophrenia.
    No preview · Article · Oct 2006 · Neuropharmacology
  • Kunio Yui · Yasushi Kajii · Toru Nishikawa
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    ABSTRACT: Spontaneous recurrence of methamphetamine- or amphetamine-induced paranoid hallucinatory psychosis (i.e., flashbacks) occasionally occurs in response to non-specific mild stress in drug-free patients with a history of methamphetamine- or amphetamine-induced psychosis. Stress sensitization associated with noradrenergic hyperactivity and increased dopamine release may be related to this flashbacks. Stressful frightening experiences as well as fear-related paranoid-hallucinatory states during methamphetamine use may be related to these stress sensitization. Robust noradrenergic hyperactivity with increased dopamine release may predicts subsequent flashback episodes. Schizophrenia-like symptoms (e.g., passivity phenomena, Gedankenlautwerden, and thought disorder such as circumstantiality and egorrhea symptoms) appear to develop related to dopaminergic hyperactivity. One of the dopamine receptor-encoding genes DRD2, TaqIA A1/A1 type, with which reduced density of the D2 receptor is associated, reduces to the risk of development of flashbacks. Stress sensitization has been proposed as a key step in the progression from vulnerability to an overt paranoid-hallucinatory states, so that schizophrenia and flashbacks due to previous methamphetamine psychosis shares common underlying mechanisms of stress sensitization. Compared to flashbacks due to previous methamphetamine psychosis, psychedelic drug flashbacks are the recurrence of a perception learned while an individual is experiencing high anxiety levels, and thus recur in anxiety-related situations. Anxiety or fear during drug use is an important factor in the development of flashbacks due to previous methamphetamine psychosis and also psychedelic drug flashbacks. Dopaminergic and glutamatergic neural circuits including the striatum, nucleus accumbens and prefrontal cortex play an important role in the development of psychostimulant-induced long-lasting behavioral sensitization. Immediate early genes expression in the particular brain regions affected by the psychostimulants is involved in this process. Furthermore, recent advances in molecular analysis could shed light on the fundamental mechanism involved, by identifying specific participating molecules such as delta FosB, NAC1, G-protein b1 subunit and methamphetamine-responsive transcript 1b.
    No preview · Article · Aug 2006 · Current Psychiatry Reviews
  • Ko Fujiyama · Yasushi Kajii · Shuichi Hiraoka · Toru Nishikawa
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    ABSTRACT: The present work was conducted to obtain clues for the possible roles of a novel stimulant-inducible gene mrt1 (methamphetamine-responsive transcript 1) encoding a PDZ-PX protein in stimulant-induced behavioral sensitization. In the young adult rats, repeated daily treatment with methamphetamine (4 mg/kg, intraperitoneally, once a day) for 5 days caused an enhanced behavioral response to methamphetamine: behavioral sensitization. The 5-day intermittent administration of MAP upregulated the basal expression of mrt1 transcripts and eliminated the increasing effects of a challenge dose of MAP (1.6 mg/kg, i.p.) or cocaine (30 mg/kg, i.p.) on mrt1 expression on day 14 of withdrawal in the neocortex that has been considered to be composed of a neuron circuit implicated in the sensitization phenomenon. In contrast, the basal expression of other stimulant-inducible and plasticity-related genes arc and homer1a and the ability of MAP or cocaine challenge to augment the amounts of their transcripts were not affected by the repeated MAP regimen in the cortical area. These findings suggest the differential regulation by stimulant of neocortical mrt1, arc, and homer1a expression in the behaviorally sensitized animals and supports the view that stimulant induction of mrt1 may be involved in the early molecular signalings for stimulant sensitization.
    No preview · Article · Sep 2003 · Synapse
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    ABSTRACT: Single or repeated exposure to psychostimulants such as amphetamines and cocaine after postnatal week 3 leads to an enduring enhancement in the psychotomimetic responses elicited by a subsequent challenge of a stimulant in rodents. This behavioral sensitization phenomenon has been considered to be the neural consequences of stimulant-induced alterations in gene expression in the brain after a critical period of postnatal development. Using a differential cloning technique, RNA arbitrarily primed PCR, we have now identified from the rat neocortex a novel and developmentally regulated methamphetamine (MAP)-inducible gene mrt1 (MAP responsive transcript 1). mrt1 encodes two major types of PDZ- and PX-domains containing proteins of approximately 62 kDa in size with different carboxy termini, Mrt1a and Mrt1b. The mrt1 mRNAs for Mrt1a, mrt1a, and for Mrt1b, mrt1b, are predominantly expressed in various brain regions and the testes, respectively. Acute MAP injection upregulated mrt1b expression in the neocortex after postnatal week 3 in a D1 receptor antagonist-sensitive manner without affecting mrt1a expression. This upregulation was mimicked by another stimulant, cocaine, whereas pentobarbital and D1 antagonist failed to change the mrt1b transcript levels. Moreover, repeated daily treatment of MAP, but not MAP plus D1 antagonist, for 5 days caused an augmentation of the basal expression of mrt1b 2 and 3 weeks after the drug discontinuation. These late-developing, cocaine-crossreactive, D1 antagonist-sensitive and long-term regulations of mrt1b by MAP are similar to the pharmacological profiles of stimulant-induced behavioral sensitization, and therefore may be associated with the initiation and/or maintenance of the long-term neuronal adaptation.
    Preview · Article · May 2003 · Molecular Psychiatry
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    ABSTRACT: To obtain insight into the molecular mechanisms underlying the metabolism and functions of endogenous -serine, we have explored -serine-regulated transcripts in the neocortex of the infant rat treated with acute -serine administration by using an RNA fingerprinting technique. Cloning and sequence analysis of the corresponding cDNAs to the identified transcripts have revealed that the dsr-1 (-serine responsive transcript-1) mRNA is presumed to contain a novel sequence at the 5′-region, while the 631-base nucleotide sequence of its 3′-end is identical with that of rat M9.2 mRNA encoding a subunit of vacuolar type proton-ATPase. The predicted two open reading frames and their deduced amino acid sequences suggest that the dsr-1 product has a membrane spanning domain. The dsr-1 transcript was detected as a single band around 2.1 kb on the Northern blot. RT-PCR analyses have indicated that the dsr-1 transcript is expressed predominantly in the brain, lung, and testis, and that acute intraperitoneal injection of -serine significantly upregulates dsr-1 expression in the neocortex 3 and 15 h later without affecting the levels of the M9.2 gene transcript. These results suggest that dsr-1 products may be involved in the -serine-related metabolic or signaling pathways in mammalian brains.
    No preview · Article · Mar 2001 · Biochemical and Biophysical Research Communications
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    ABSTRACT: We report here the isolation and characterization of cDNA clones for a novel isoform of CDCrel-1 septin, termed CDCrel-1A, with a different 5' end sequence from the transcripts encoding the known CDCrel-1 (designated as CDCrel-1F) in the developing rat neocortex. Alternative polyadenylation site selections resulted in various transcripts for CDCrel-1A including the fusion forms with another gene, platelet glycoprotein Ibbeta (GPIbbeta). Expression of the distinct transcripts encoding CDCrel-1A and CDCrel-1F increased and decreased, respectively, from the infant to adult period. Therefore CDCrel-1A might be a major form of the CDCrel-1 septin in the adult neocortex of mammals.
    No preview · Article · Aug 2000 · Biochemical and Biophysical Research Communications

  • No preview · Article · Dec 1998 · Neuroscience Research

  • No preview · Article · Dec 1998 · Neuroscience Research
  • Takanori Hashimoto · Yasushi Kajii · Toru Nishikawa
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    ABSTRACT: We have studied in the rat the effects of acute subcutaneous injection of psychotomimetics including methamphetamine (MAP), cocaine and phencyclidine (PCP) on the expression of a brain plasticity-related molecule, tissue plasminogen activator (tPA) mRNA, using non-radioactive in situ hybridization histochemistry. In addition to the constitutive expression of tPA mRNA in cerebellar Purkinje cells, ventricular ependymal cells and meningeal blood vessel-associated cells, MAP (1-4 mg/kg), cocaine (30 mg/kg) and PCP (1.25-5 mg/kg) caused a transient and dose-dependent induction of the transcript with its peak at 3 h postinjection in a group of neurons of the medial and insular prefrontal cortices, and the piriform cortex. Another indirect dopamine agonist nomifensine (20-40 mg/kg) mimicked the tPA mRNA induction in the prefrontal cortical areas. Moreover, MAP induction of tPA mRNA was markedly inhibited by pretreatment with a D1 (R(+)-SCH23390: R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-be nza zepine hydrochloride) or a D2 (haloperidol) dopamine receptor-preferring antagonist. Intramedial striatum, but not intrathalamic, application of a fluorescent tracer, fluorogold, retrogradely labelled the cortical cells expressing tPA mRNA. The present results suggest that acute injections of the above psychotomimetic drugs may induce tPA mRNA in a group of the prefrontal cortical neurons that project to the medial striatum. This tPA mRNA expression may be due to the activation of the dopamine neurotransmission. Because it is well documented that single or repeated administration of methamphetamine, cocaine and PCP produces enduring changes in responses to these drugs in humans and experimental animals (e.g. behavioural sensitization), the psychotomimetic-induction of tPA mRNA could be implicated in an initial step in the plastic rearrangements in the neuronal circuits underlying long-lasting changes in behavioural expression.
    No preview · Article · Dec 1998 · European Journal of Neuroscience
  • Takanori Hashimoto · Yasushi Kajii · Toru Nishikawa

    No preview · Article · Dec 1997 · Neuroscience Research
  • Takanori Hashimoto · Yasushi Kajii · Toru Nishikawa

    No preview · Article · Dec 1996 · Neuroscience Research

Publication Stats

216 Citations
56.39 Total Impact Points


  • 2003-2014
    • Tokyo Medical and Dental University
      • Department of Psychiatry and Behavioral Science
      Edo, Tokyo, Japan
  • 2013
    • Mitsubishi Tanabe Pharma Corporation
      Ōsaka, Ōsaka, Japan
  • 1998-2003
    • National Center of Neurology and Psychiatry
      • Department of Mental Disorder Research
      Кодаиры, Tōkyō, Japan