担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Adrenergic receptors (ADRs) are widely distributed in the peripheral and central nervous systems. We previously reported that L-3,4-dihydroxyphenylalanine (L-DOPA), the precursor of dopamine, sensitizes adrenergic α1 receptor (ADRA1) through a G protein-coupled receptor GPR143. Chimeric analysis, in which the transmembrane (TM) domains of GPR143 were replaced with those of GPR37, revealed that the second TM region was essential for the potentiation of phenylephrine-induced extracellular signal-regulated kinase (ERK) phosphorylation by GPR143. In HEK293T cells expressing ADRA1B, phenylephrine-induced ERK phosphorylation was augmented by the co-expression of GPR143, compared to the mock vector. Immunoprecipitation analysis revealed that a synthetic transactivator of the transcription peptide fused with TM2 of GPR143 (TAT-TM2) disrupts the interaction between GPR143 and ADRA1B. This TAT-TM2 peptide suppressed the augmentation of phenylephrine-induced ERK phosphorylation by GPR143 in HEK293T cells co-expressing ADRA1B and GPR143. These results indicate that the interaction between GPR143 and ADRA1B is required for the potentiation of ADRA1B-mediated signaling by GPR143. The TM2 region of GPR143 is a crucial dimeric interface for the functional coupling between ADRA1B and GPR143.

DOI： 10.1248/bpb.b23-00217

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In the central nervous system, the A6 noradrenaline (NA) and the B3 serotonin (5-HT) cell groups are well-recognized players in the descending antinociceptive system, while other NA/5-HT cell groups are not well characterized. A5/A7 NA and B2 5-HT cells project to the spinal horn and form descending pathways. We recorded G-CaMP6 green fluorescence signal intensities in the A5/A7 NA and the B2 5-HT cell groups of awake mice in response to acute tail pinch stimuli, acute heat stimuli, and in the context of a non-noxious control test, using fiber photometry with a calcium imaging system. We first introduced G-CaMP6 in the A5/A7 NA or B2 5-HT neuronal soma, using transgenic mice carrying the tetracycline-controlled transactivator transgene under the control of either a dopamine β-hydroxylase or a tryptophan hydroxylase-2 promoters and by the site-specific injection of adeno-associated virus (AAV-TetO(3G)-G-CaMP6). After confirming the specific expression patterns of G-CaMP6, we recorded G-CaMP6 green fluorescence signals in these sites in awake mice in response to acute nociceptive stimuli. G-CaMP6 fluorescence intensity in the A5, A7, and B2 cell groups was rapidly increased in response to acute nociceptive stimuli and soon after, it returned to baseline fluorescence intensity. This was not observed in the non-noxious control test. The results indicate that acute nociceptive stimuli rapidly increase the activities of A5/A7 NA or B2 5-HT neurons but the non-noxious stimuli do not. The present study suggests that A5/A7 NA or B2 5-HT neurons play important roles in nociceptive processing in the central nervous system. We suggest that A5/A7/B2 neurons may be new therapeutic targets. All performed procedures were approved by the Institutional Animal Use Committee of Kagoshima University (MD17105) on February 22, 2018.

DOI： 10.4103/1673-5374.322465

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary hypertension (PH) is a severe and progressive disease that causes elevated right ventricular systolic pressure, right ventricular hypertrophy and ultimately right heart failure. However, the underlying pathophysiologic mechanisms are poorly understood. We previously showed that 3,4-l-dihydroxylphenyalanine (DOPA) sensitizes vasomotor response to sympathetic tone via coupling between the adrenergic receptor alpha1 (ADRA1) and a G protein-coupled receptor 143 (GPR143), a DOPA receptor. We investigated whether DOPA similarly enhances ADRA1-mediated contraction in pulmonary arteries isolated from rats, and whether GPR143 is involved in the PH pathogenesis. Pretreating the isolated pulmonary arteries with DOPA 1 μM enhanced vasoconstriction in response to phenylephrine, an ADRA1 agonist, but not to U-46619, a thromboxane A2 agonist or endothelin-1. We generated Gpr143 gene-deficient (Gpr143-/y) rats, and confirmed that DOPA did not augment phenylephrine-induced contractile response in Gpr143-/y rat pulmonary arteries. We utilized a rat model of monocrotaline (MCT)-induced PH. In the MCT model, the right ventricular systolic pressure was attenuated in the Gpr143-/y rats than in WT rats. Phenylephrine-induced cell migration and proliferation were also suppressed in Gpr143-/y pulmonary artery smooth muscle cells than in WT cells. Our result suggests that GPR143 is involved in the PH pathogenesis in the rat models of PH.

DOI： 10.1016/j.jphs.2021.11.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press ({OUP})  

Neurogenesis occurs in the hippocampus throughout life and is implicated in various physiological brain functions such as memory encoding and mood regulation. L-3,4-dihydroxyphenylalanine (L-DOPA) has long been believed to be an inert precursor of dopamine. Here, we show that L-DOPA and its receptor, GPR143, the gene product of ocular albinism 1, regulate neurogenesis in the dentate gyrus (DG) in a dopamine-independent manner. L-DOPA at concentrations far lower than that of dopamine promoted proliferation of neural stem and progenitor cells in wild-type mice under the inhibition of its conversion to dopamine; this effect was abolished in GPR143 gene-deficient (Gpr143-/y) mice. Hippocampal neurogenesis decreased during development and adulthood, and exacerbated depression-like behavior was observed in adult Gpr143-/y mice. Replenishment of GPR143 in the DG attenuated the impaired neurogenesis and depression-like behavior. Our findings suggest that L-DOPA through GPR143 modulates hippocampal neurogenesis, thereby playing a role in mood regulation in the hippocampus.

DOI： 10.1093/stmcls/sxab013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The orexinergic system plays a significant role in regulating proper sleep/wake maintenance. Dual orexin receptor antagonist (DORA) is widely prescribed for insomnia symptoms. The antagonist acts on orexin 1 and 2 receptors located in certain brain areas, including the locus coeruleus and dorsal raphe. Nevertheless, its effects on monoamine-related gene expression remain unclear. Here, we measured the expression levels of monoamine-related genes in DORA-treated mice. DORA treatment significantly affected overall levels of noradrenalin transporter/monoamine oxidases A mRNA expression in the hippocampus. Our findings suggest that DORA contributes to noradrenalin-related gene expression regulation in the central nervous system.

DOI： 10.1016/j.jphs.2020.12.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nicotine exerts its reinforcing actions by activating nicotinic acetylcholine receptors (nAChRs), but the detailed mechanisms remain unclear. Nicotine releases 3, 4-dihydroxyphenylalanine (DOPA), a neurotransmitter candidate in the central nervous system. Here, we investigated the distribution of GPR143, a receptor of DOPA, and nAChR subunits in the nigrostriatal and mesolimbic regions. We found GPR143 mRNA-positive cells in the striatum and nucleus accumbens. Some of them were surrounded by tyrosine hydroxylase (TH)-immunoreactive fibers. There were some GPR143 mRNA-positive cells coexpressing TH, and nAChR subunit α4 or α7 in the substantia nigra and ventral tegmental area. These findings suggest that DOPA-GPR143 signaling may be involved in the nicotine action in the nigrostriatal and mesolimbic dopaminergic systems.

DOI： 10.1016/j.neures.2020.08.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

l-3,4-dihydroxyphenylalanine (l-DOPA) is a candidate neurotransmitter. l-DOPA is released by nicotine through nicotinic receptors. Recently, G-protein coupled receptor GPR143, was identified as a receptor for l-DOPA. In this study, genetic association studies between GPR143 genetic polymorphisms and smoking behaviors revealed that the single-nucleotide polymorphism rs6640499, in the GPR143 gene, was associated with traits of smoking behaviors in Japanese individuals. In Gpr143 gene-deficient mice, nicotine-induced hypolocomotion and rewarding effect were attenuated compared to those in wild-type mice. Our findings suggest the involvement of GPR143 in the smoking behaviors.

DOI： 10.1016/j.jphs.2020.07.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Orexinergic neurons, which are closely associated with narcolepsy, regulate arousal and reward circuits through the activation of monoaminergic neurons. Psychostimulants as well as 5-HT-related compounds have potential in the treatment of human narcolepsy. Previous studies have demonstrated that orexin receptor antagonists as well as orexin deficiencies affect the pharmacological effects of psychostimulants. However, little information is available on the consequences of psychostimulant use under orexin deficiency. Therefore, the present study was designed to investigate the abuse liability of psychostimulants in orexin knockout (KO) mice. In the present study, conditioned place preferences induced by methamphetamine and methylphenidate were not altered in orexin KO mice. Interestingly, we found that MDMA induced a conditioned place preference in orexin KO mice, but not in wild type (WT) mice. In addition, MDMA produced methylphenidate/methamphetamine-like discriminative stimulus effects in orexin KO mice, but not WT mice. Increases in 5-HT and dopamine release in the nucleus accumbens induced by MDMA were not altered by knockout of orexin; the steady-state level of G protein activation was higher in the limbic forebrain of orexin KO mice. In substitution tests using a drug discrimination procedure, substitution of 5-HT1A receptor agonist for the discriminative stimulus effects of methylphenidate was enhanced in orexin KO mice. These findings indicate that the orexinergic system is involved the rewarding effects of psychostimulants. However, there is a risk of establishing rewarding effects of psychostimulants even under orexin deficiency. On the other hand, deficiencies in orexin may enhance the abuse liability of MDMA by changing a postsynaptic signal transduction accompanied by changes in discriminative stimulus effects themselves.

DOI： 10.1016/j.bbr.2020.112802

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Some psychiatric diseases are associated with disruptions in the circadian clock system. Ziprasidone (ZIP), a second-generation antipsychotic, is widely used for psychiatry-related pharmacotherapy but its mechanism has not been clearly elucidated. We measured clock gene fluctuation patterns in the hippocampus and the amygdala in ZIP-treated mice. ZIP significantly increased Per1, Per2, and Bmal1 mRNA 2 h after the lights were turned off (ZT14) in the hippocampus, but not in the amygdala. These results suggest that ZIP might affect clock gene regulation, which could represent the pathway underlying symptom amelioration.

DOI： 10.1016/j.jphs.2020.06.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The roles of serotonergic and noradrenergic signaling in nociceptive processing in the central nervous system are well known. However, dopaminergic signaling is also relevant to various physical functions, including nociception. The zona incerta is a subthalamic nucleus in which the A13 dopaminergic cell group resides, but how this A13 group affects nociceptive processing remains unknown. Recently, we showed that acute nociceptive stimuli rapidly induce the activity of A10 (ventral tegmental area) dopamine neurons via fiber photometry. In this study, we measured the activity of A13 dopaminergic neurons in response to acute nociceptive stimuli using the same system. Adeno-associated viruses (AAV-CAG-FLEX-G-CaMP6 and AAV-CAG-FLEX-mCherry) were unilaterally injected into the A13 site in transgenic mice carrying a dopamine transporter promotor-regulated Cre recombinase transgene to specifically introduce G-CaMP6/mCherry into A13 dopaminergic cell bodies through site-specific infection. We measured G-CaMP6/mCherry fluorescence intensity in the A13 site to acute nociceptive stimuli (pinch stimulus and heat stimulus). These stimuli significantly induced a rapid increase in G-CaMP6 fluorescence intensity, but non-nociceptive control stimuli did not. In contrast, mCherry fluorescence intensity was not significantly changed by nociceptive stimuli or non-nociceptive stimuli. Our finding is the first report to measure the activity of A13 dopaminergic neurons to aversive stimuli. A13 dopaminergic neurons project to the periaqueductal gray and the central nucleus of the amygdala, which are both well known as key regions in nociceptive processing. Therefore, together with our A10 study, our results indicate that A13 dopaminergic neurons play important roles in nociceptive processing.

DOI： 10.1186/s13041-020-00600-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Levodopa (L-Dopa), the current main treatment for PD, reduces PD symptoms by partially replacing dopamine, but it does not slow neurodegeneration. Recent studies have evidenced that neuroinflammatory processes contribute to the degeneration of dopaminergic neurons in the SNc under cytopathic conditions, while other lines of inquiry have implicated phosphorylation of collapsin response mediator protein 2 (CRMP2) as a causal factor in axonal retraction after neural injury. We recently reported on the therapeutic effect of lanthionine ketimine ester (LKE) which associates with CRMP2 following axonal injury in the spinal cord. In the present study, we report that LKE protects SNc dopaminergic neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) challenge, a common model for PD, and reduces the number of activated microglia proximal to the damaged SNc. The results also show that MPTP-induced motor impairment was suppressed in LKE treatment. Furthermore, the results show that LKE inhibits the elevation of CRMP2 phosphorylation in dopaminergic neurons in the SNc after MPTP injection. These data suggest that modification of CRMP2 phosphorylation and suppression of microglial activation with LKE administration may represent a novel strategy for slowing progress of pathological processes in PD.

DOI： 10.1016/j.jns.2020.116802

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pancreatic intraepithelial neoplasia (PanIN), the most common premalignant lesion of the pancreas, is a histologically well-defined precursor to invasive pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms underlying the progression of PanINs have not been fully elucidated. Previously, we demonstrated that the expression of collapsin response mediator protein 4 (CRMP4) in PDAC was associated with poor prognosis. The expression of CRMP4 was also augmented in a pancreatitis mouse model. However, the role of CRMP4 in the progression of PanIN lesions remains uncertain. In the present study, we examined the relationship between CRMP4 expression and progression of PanIN lesions using genetically engineered mouse models. PanIN lesions were induced by peritoneal injection of the cholecystokinin analog caerulein in LSL-KRASG12D; Pdx1-Cre (KC-Crmp4 wild-type, WT) mice and LSL-KRASG12D; Pdx1-Cre; Crmp4-/- (KC-Crmp4 knockout, KO) mice. We analyzed pancreatic tissue sections from these mice and evaluated PanIN grade by hematoxylin and eosin staining. CRMP4 expression was examined and the cellular components assessed by immunohistochemistry using antibodies against CRMP4, CD3, and α-smooth muscle actin (SMA). The incidence of high-grade PanIN in KC-Crmp4 WT mice was higher than that in KC-Crmp4 KO animals. CRMP4 was expressed not only in epithelial cells but also in αSMA-positive cells in stromal areas of PanIN lesions. The CRMP4 expression in stromal areas correlated with PanIN grade in WT mice. These results suggested that the expression of CRMP4 in stromal cells may underlie the incidence or progression of PanIN.

DOI： 10.1016/j.tranon.2020.100746

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記述言語：英語  

Nociception is important perception that has harmful influence on daily life of humans. As to main pain management system, some descending pathways are called descending antinociceptive systems (DAS). As main pathways of DAS, it is well known that dorsal raphe (B6/B7) - rostral ventromedial medulla (B3) - spinal dorsal horn includes serotonergic system. However, possible role of supralemniscal (B9) serotonin (5-HT) cell group in pain management is still open question. In this study, we measured activities of B9 5-HT neuronal cell bodies and B9 5-HT neuron-derived axons located in the locus coeruleus (LC) and ventral tegmental area (VTA), which are also main players of pain management, using fiber photometry system. We introduced the G-CaMP6 in B9 5-HT neurons using transgenic mice carrying a tetracycline-controlled transactivator transgene (tTA) under the control of a tryptophan hydroxylase-2 (TPH2) promoter and site-specific injection of adeno associated virus (AAV-TetO(3G)-G-CaMP6). After confirmation of specific expression of G-CaMP6 in the target population, G-CaMP6 fluorescence intensity in B9 group and LC/VTA groups was measured in awake mice exposed to acute tail pinch and heat stimuli. G-CaMP6 fluorescence intensity rapidly increased by both stimuli in all groups, but not significantly reacted by nonnociceptive control stimuli. The present results clearly indicate that acute nociceptive stimuli cause a rapid increase in the activities of B9-LC/B9-VTA 5-HTergic pathways, suggesting that B9 5-HT neurons play important roles in nociceptive processing.

DOI： 10.1186/s13041-020-0553-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.nbd.2019.104603

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DOI： 10.1016/j.jphs.2019.09.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fphar.2019.01119

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DOI： 10.1016/j.neures.2018.12.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/gtc.12651

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1172/jci.insight.90903

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

Background: Extremely preterm infants frequently have patent ductus arteriosus (PDA). Recent recommendations include immediately beginning amino acid supplementation in extremely preterm infants. However, the effect of amino acids on closure of the ductus arteriosus (DA) remains unknown.
Methods and Results: Aminogram results in human neonates at day 2 revealed that the plasma glutamate concentration was significantly lower in extremely preterm infants (<28 weeks' gestation) with PDA than in those without PDA and relatively mature preterm infants (28-29 weeks gestation). To investigate the effect of glutamate on DA closure, glutamate receptor expression in fetal rats was examined and it was found that the glutamate inotropic receptor, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type subunit 1 (GluR1), mRNA was highly expressed in the DA compared to the aorta on gestational day 19 (preterm) and gestational day 21 (term). GluR1 proteins were co-localized with tyrosine hydroxylase-positive autonomic nerve terminals in the rat and human DA. Intraperitoneal administration of glutamate increased noradrenaline production in the rat DA. A whole-body freezing method demonstrated that glutamate administration induced DA contraction in both preterm (gestational day 20) and term rat fetuses. Glutamate-induced DA contraction was attenuated by the calcium-sensitive GluR receptor antagonist, NASPM, or the adrenergic receptor a1 blocker, prazosin.
Conclusions: These data suggest that glutamate induces DA contraction through GluR-mediated noradrenaline production. Supplementation of glutamate might help to prevent PDA in extremely preterm infants.

DOI： 10.1253/circj.CJ-16-0649

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in fropioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain. (C) 2016 Published by Elsevier B.V.

DOI： 10.1016/j.ejps.2016.03.019

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Through its conversion to dopamine by aromatic L-amino acid decarboxylase (AADC), L-3,4-dihydroxyphenylalanine (L-DOPA) replenishes depleted brain dopamine in Parkinson's disease patients. We recently identified GPR143 as a candidate receptor for L-DOPA. In this study, we investigated the behavioral actions of L-DOPA in wild type (wt) and Gpr143-deficient mice. L-DOPA dose-dependently (10e100 mg/kg, i.p.) induced ptosis under treatment with 3-hydroxybenzylhydrazine, a centrally acting AADC inhibitor. This effect was not mimicked by 3-O-methyldopa. L-DOPA-induced ptosis in Gpr143-deficient mice to a similar extent as in wt mice. These results suggest that L-DOPA induces ptosis in a GPR143-independent fashion in mice. (C) 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license

DOI： 10.1016/j.jphs.2016.08.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Orexin knockout (KO) mice exhibit a phenotype that is similar to human narcolepsy, and monoamine-related compounds, such as psychostimulants and 5-HT uptake inhibitors, have been used for the treatment of narcoleptic disorders. However, little information is available regarding the pathophysiological features of orexin KO mice, particularly with respect to their narcoleptic-like disorder and how it is affected by monoamine-related compounds.
The present study was designed to investigate both the nature of the neuronal changes in orexin KO mice and the therapeutic effects of monoamine-related compounds on the sleep disorder in orexin KO mice.
A decrease in locomotor activity in the dark phase was observed in orexin KO mice, and psychostimulants and 5-HT-related compounds, such as 8-OH-DPAT (5-HT1A receptor agonist) and DOI (5-HT2 receptor agonist), inhibited this hypolocomotion. We also found that 5-HT1A receptor mRNA levels, but not those for 5-HT2 or dopamine receptors, were significantly decreased in the prefrontal cortex of orexin KO mice in the dark period and were accompanied by compromising the increase in 5-HT metabolite levels. In addition, the sleep disorder in orexin KO mice, as analyzed by a polysomnography during the dark period, was completely normalized by 8-OH-DPAT.
These results suggest that a dysfunction of 5-HT1A receptors is involved in the narcoleptic-like sleep dysfunction in orexin KO mice, and such dysfunction may participate in orexin deficiency-induced sleep disorders. Further, the use of 5-HT1A receptor agonist could be useful for treating the sleep disorder under a deficiency of orexin.

DOI： 10.1007/s00213-016-4282-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Typical abused drug-induced behavioral changes are ordinarily mediated by the mesolimbic dopaminergic system and even the phenotypes of behavior are different from each other. However, the mechanisms that underlie the behavioral changes induced by these abused drugs have not yet been elucidated. The present study was designed to investigate the mechanisms that underlie how abused drugs induce distinct behavioral changes using neurochemical as well as behavioral techniques in rats. Methamphetamine (2 mg/kg) more potently increased dopamine release from the striatum more than that from the nucleus accumbens. In contrast, the administration of morphine (10 mg/kg) produced a significant increase in the release of dopamine from the nucleus accumbens, but not the striatum, which is accompanied by a decrease in the release of GABA in the ventral tegmental area. These findings indicate that morphine and methamphetamine differentially regulate dopaminergic systems to produce behavioral changes, even though both drugs have abuse potential through activation of the mesolimbic dopaminergic system. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuroscience.2016.01.043

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/adb.12169

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Oa1 is the casual gene for ocular albinism-1 in humans. The gene product OA1, alternatively designated as GPR143, belongs to G-protein coupled receptors. It has been reported that OA1 is a specific receptor for 3, 4-dihydroxy- L-phenylalanine (DOPA) in retinal pigmental epithelium where DOPA facilitates the pigmentation via OA1 stimulation. We have recently shown that OA1 mediates DOPA-induced depressor response in rat nucleus tractus solitarii. However, the distribution and function of OA1 in other regions are largely unlmown. We have generated OA1 knockout mice and examined OA1 expression in both neuronal and non-neuronal tissues by immunohistochemical analyses using anti-mouse OA1 monoclonal antibodies. In the telencephalon, OA1 was expressed in cerebral cortex and hippocampus. Predominant expression of OA1 was observed in the pyramidal neurons in these regions. OA1 was also expressed in habenular nucleus, hypothalamus, substantia nigra, and medulla oblongata. The expression of OA1 in the nucleus tiactus solitarii of medulla oblongata may support the reduction of blood pressure by the microinjection of DOPA into this region. Outside of the nervous system, OA1 was expressed in heart, lung, liver, kidney and spleen. Abundant expression was observed in the renal tubules and the splenic capsules. These peripheral regions are innervated by numerous sympathetic nerve endings. In addition, substantia nigra contains a large population of dopaminergic neurons. Thus, the immunohistochemical analyses suggest that OA1 may modulate the monoaminergic functions in both peripheral and central nervous systems. (C) 2015 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2015.01.020

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

L-3,4-Dihydroxyphenylalanine (DOPA) has been believed to be a precursor of dopamine, and itself being an inert amino acid. Previously, we have proposed DOPA as a neurotransmitter candidate in the central nervous system (CNS). Recent findings have suggested DOPA as an endogenous agonist of a G-protein coupled receptor, ocular albinism 1 gene product (OA1), which is highly expressed in the retinal pigmental epithelium. However, whether OA1 functions as a receptor for DOPA in vivo, and whether this receptor-ligand interaction is responsible for a wide variety of DOPA actions have not been determined yet. To gain insight into the functional implication of OA1, we perform immunohistochemical examination with anti-OA1 antibody to localize OA1 in the adult rat brain. We observed OA1 immunoreactive cells in the hippocampus, cerebral cortex, cerebellum cortex, striatum, substantia nigra, hypothalamic median eminence and supraoptic nucleus, nucleus tractus solitarii and caudal ventrolateral medulla and rostral ventrolateral medulla, medial habenular nucleus and olfactory bulb. This study reveals, for the first time, the unique distribution pattern of OA1-immunoreactive neurons and/or cells in the rat CNS. (C) 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2014.07.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Long-term exposure to zolpidem induces drug dependence, and it is well known that the balance between the GABAergic and glutamatergic systems plays a critical role in maintaining the neuronal network In the present study, we investigated the interaction between GAB(AA) receptor alpha 1 subunit and mGlu(5) receptor in the limbic forebrain including the N.Acc. after treatment with zolpidem for 7 clays. mGlu(5) receptor protein levels were significantly increased after treatment with zolpidem for 7 days, and this change was accompanied by the up regulation of phospholipase C beta 1 and calcium/calmodulin-dependent protein kinase II alpha, which are downstream of mGlu(5) receptor in the limbic forebrain. To confirm that mGlu(5) receptor is directly involved in dopamine-related behavior in mice following chronic treatment with zolpidem, we measured morphine-induced hyperlocomotion after chronic treatment with zolpidem in the presence or absence of an mGlu(5) receptor antagonist. Although chronic treatment with zolpidem significantly enhanced morphine-induced hyperlocomotion, this enhancement of morphine-induced hyperlocomotion was suppressed by treating it with the mGlu(5) receptor antagonist MPEP. These results suggest that chronic treatment with zolpidem caused neural plasticity in response to activation of the mesolimbic dopaminergic system accompanied by an increase in mGlu(5) receptor. (C) 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejphar.2014.06.001

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記述言語：英語   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

L-3,4-Dihydroxyphenylalanine (DOPA) is the metabolic precursor of dopamine, and the single most effective agent in the treatment of Parkinson's disease. One problem with DOPA therapy for Parkinson's disease is its cardiovascular side effects including hypotension and syncope, the underlying mechanisms of which are largely unknown. We proposed that DOPA is a neurotransmitter in the central nervous system, but specific receptors for DOPA had not been identified. Recently, the gene product of ocular albinism 1 (OA1) was shown to possess DOPA-binding activity. It was unknown, however, whether or not OA1 is responsible for the actions of DOPA itself. Immunohistochemical examination revealed that OA1 was expressed in the nucleus tractus solitarii (NTS). OA1-positive cells adjacent to tyrosine hydroxylase positive cell bodies and nerve fibers were detected in the depressor sites of the NTS. OA1 knockdown using oal-specific shRNA-adenovirus vectors in the NTS reduced the expression levels of OA1 in the NTS. The prior injection of the shRNA against OA1 suppressed the depressor and bradycardic responses to DOPA but not to glutamate in the NTS of anesthetized rats. Thus OA-1 is a functional receptor of DOPA in the NTS, which warrants reexamination of the mechanisms for the therapeutic and untoward actions of DOPA.

DOI： 10.1254/jphs.14R03CR

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and PurposeL-DOPA is generally considered to alleviate the symptoms of Parkinson's disease by its conversion to dopamine. We have proposed that DOPA is itself a neurotransmitter in the CNS. However, specific receptors for DOPA have not been identified. Recently, the gene product of ocular albinism 1 (OA1) was found to exhibit DOPA-binding activity. Here, we have investigated whether OA1 is a functional receptor of DOPA in the nucleus tractus solitarii (NTS).
Experimental ApproachWe examined immunohistochemical expression of OA1 in the NTS, and the effects of DOPA microinjected into the depressor sites of NTS on blood pressure and heart rate in anaesthetized rats, with or without prior knock-down of OA1 in the NTS, using shRNA against OA1.
Key ResultsUsing a specific OA1 antibody, OA1-positive cells and nerve fibres were found in the depressor sites of the NTS. OA1 expression in the NTS was markedly suppressed by microinjection into the NTS of adenovirus vectors carrying the relevant shRNA sequences against OA1. In animals treated with OA1 shRNA, depressor and bradycardic responses to DOPA, but not those to glutamate, microinjected into the NTS were blocked. Bilateral injections into the NTS of DOPA cyclohexyl ester, a competitive antagonist against OA1, suppressed phenylephrine-induced bradycardic responses without affecting blood pressure responses.
Conclusion and ImplicationsOA1 acted as a functional receptor for DOPA in the NTS, mediating depressor and bradycardic responses. Our results add to the evidence for a central neurotransmitter role for DOPA, without conversion to dopamine.

DOI： 10.1111/bph.12459

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1124/jpet.113.204313

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Benzodiazepines are commonly used as sedatives, sleeping aids, and anti-anxiety drugs. However, chronic treatment with benzodiazepines is known to induce dependence, which is considered related to neuroplastic changes in the mesolimbic system. This study investigated the involvement of K+-Cl co-transporter 2 (KCC2) in the sensitization to morphine-induced hyperlocomotion after chronic treatment with zolpidem [a selective agonist of -aminobutyric acid A-type receptor (GABAAR) 1 subunit]. In this study, chronic treatment with zolpidem enhanced morphine-induced hyperlocomotion, which is accompanied by the up-regulation of KCC2 in the limbic forebrain. We also found that chronic treatment with zolpidem induced the down-regulation of protein phosphatase-1 (PP-1) as well as the up-regulation of phosphorylated protein kinase C (pPKC). Furthermore, PP-1 directly associated with KCC2 and pPKC, whereas pPKC did not associate with KCC2. On the other hand, pre-treatment with furosemide (a KCC2 inhibitor) suppressed the enhancing effects of zolpidem on morphine-induced hyperlocomotion. These results suggest that the mesolimbic dopaminergic system could be amenable to neuroplastic change through a pPKC-PP-1-KCC2 pathway by chronic treatment with zolpidem.

DOI： 10.1111/jnc.12258

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記述言語：日本語  

J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

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記述言語：日本語   出版者・発行元：日本アルコール・薬物医学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

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記述言語：日本語  

J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公社)日本薬剤学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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記述言語：日本語   出版者・発行元：日本医療薬学会  

CiNii Books

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記述言語：日本語   出版者・発行元：(公社)日本薬剤師会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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会議種別：ポスター発表  

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