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Regulation of DISC1 through phosphorylation by ERK
Abstracts / Neuroscience Research 58S (2007) S1–S244
O2P-HØ2 IL-1 receptor antagonist (IL-1Ra) KO mice show
S65
O2P-HØ7 Identification of YWHAE, a gene encoding 14-3-3,
anxiety-like behavior
as a novel susceptibility gene for schizophrenia
Chisato Wakabayashi 1,2 , Yoichiro Iwakura 1 1 Laboratory of Cell Biology, University of Tokyo, Tokyo, Japan; 2 Japan Society for the Promotion of Science (JSPS), Tokyo, Japan
Takao Hikita 1 , Masashi Ikeda 2 , Shinichiro Taya 1 , Takeshi Miyakawa 3 , Kozo Kaibuchi 1 , Norio Ozaki 4 , Nakao Iwata 2 1 Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya, Japan; 2 Department of Psychiatry, Fujita Health University, Toyoake, Japan; 3 Department of Genetic Engineering and Functional Genomics, Kyoto University, Kyoto, Japan; 4 Department of Psychiatry, Nagoya University, Nagoya, Japan
It is well known that the expression of IL-1 mRNA is induced by stress. Lines of evidence show that IL-1 administration influences the release of monoamines and these effects are attenuated by the pre-administration of IL-1Ra. These results strongly suggest that IL-1 directly influences monoamine contents in the brain and trigger the mental disease, such as anxiety and depression. It is unclear, however, the precise roles of IL-1 in the development of psychological diseases. In this study, we used the IL-1Ra KO mice and examined various behavioral tests. Because of the absence of IL-1Ra, physiological levels of IL-1 in the brain may activate the receptor excessively resulting in the similar situation as stressed animals. Very interestingly, at 20 weeks, anxiety-like behavior was appeared and was ameliorated by the administration of Diazepam. Further mechanisms of the induction pathways are now fully investigating. Research funds: Grant-in-Aid for JSPS Fellows
Disrupted-In-Schizophrenia 1 (DISC1) is one of the candidate genes for the susceptibility to schizophrenia. We investigated the genetic association between DISC1 interacting molecules and schizophrenia in a Japanese population, and identified a promoter SNP for YWHAE, a gene encoding 14-3-3. The minor allele frequencies of this SNP were higher in controls. mRNA transcription and protein expression of 14-3-3 were increased in the lymphocytes of healthy control subjects harboring heterozygous and homozygous minor allele. Ywhae+/− mice showed cognitive dysfunctions that are observed in schizophrenia patients. These results suggest that YWHAE is a novel susceptibility gene to schizophrenia that works protectively. Research funds: KAKENHI 15GS0319, KAKENHI 17024024, 21st Century Centre of Excellence Program
O2P-HØ4 Chronic effects of methamphetamine, MDMA and 5-MeO-DiPT on raphe serotonergic neurons in rat organotypic mesencephalic slice culture Megumi Higuchi, Yuichi Suzuki, Takayuki Nakagawa, Shuji Kaneko Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan Recent evidence suggests the involvement of raphe serotonergic neurons in drug dependence and addiction to the psychostimulant, methamphetamine (METH), and recreational drugs such as 3,4methylenedioxymethamphetamine (MDMA) or 5-MeO-DiPT. In this study, we examined the chronic effects of METH, MDMA and 5-MeO-DiPT on serotonin release and serotonergic neurotoxicity in rat organotypic mesencephalic slice cultures containing the raphe nuclei. Acute treatment with METH and MDMA dose-dependently increased serotonin release, while 5-MeO-DiPT did not. Sustained treatment with METH or MDMA for 6 days followed by their challenge (24 h later) significantly augmented their serotonin-releasing effects. Sustained treatments with 5-MeO-DiPT decreased tissue contents of serotonin and [3 H]citalopram binding, while METH and MDMA had little effect. These results suggest that chronic treatment with METH or MDMA induces serotonergic sensitization, while 5-MeO-DiPT produces serotonergic neurotoxicity without serotonin release.
O2P-HØ5 Regulation of DISC1 through phosphorylation by ERK Shinichiro Taya, Junko Uraguchi-Asaki, Keisuke Kuroda, Kozo Kaibuchi Department of Cell Pharmacology, Nagoya University, Nagoya, Japan Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. Previously, we reported that Kinesin-1, a motor protein of anterograde axonal transport, as a novel DISC1-interacting protein. Kinesin-1 interacts with the NUDEL/LIS1/14-3-3epsilon complex or Grb2 through DISC1. The knockdown of DISC1 inhibits the accumulation of the NUDEL complex and Grb2 at the axons and axon elongation. DISC1 appears to regulate the localization of the NUDEL complex and Grb2 into the axons as a cargo receptor for axon elongation. However, it remains unknown how the functions of DISC1 are regulated. Here, we found that the phosphorylation of DISC1 was increased by treatment with a phosphatase inhibitor, Calyculin A, and this phosphorylation was canceled by treatment with an ERK inhibitor. DISC1 was directly phosphorylated by ERK in a cell-free system. The physiological meanings of DISC1 phosphorylation by ERK will be discussed. Research funds: KAKENHI (18700363) (17024024) (15GS0319)
O2P-HØ9 Chronic administration of nicotine retards the development of morphine dependency and tolerance in mice Abbas Haghparast, Nima Naderi, Abbas Khani, Amir Alizadeh, Fereshteh Motamedi Neuroscience Research Center, Shaheed Beheshti Medical University, Tehran, Iran Investigating the interaction between nicotinic and opioid receptors is of great interest to both basic mechanistic and clinical views. Eighty male mice were rendered dependent on morphine. We used repeated injection of nicotine (0.001, 0.01, 0.1, 1 and 2 mg/kg; ip) 15 min prior to each morphine application along with control groups. Tail Flick latency pre- and post-morphine injection and number of jumping after injection of naloxone (5 mg/kg; ip), 2 h after morphine application in the fourth day, were used as indexes for development of tolerance and dependency, respectively. Results showed that nicotine doses at 2, 1 and 0.1 mg/kg significantly reversed the development of tolerance. The most effective dose of nicotine that significantly decreased the number of jumping is 0.1 mg/kg. So, our study indicates that repeated injection of nicotine reverses the development of morphine tolerance and dependency. Dose–response curve of nicotine vs. decrease in development of morphine dependency interestingly does not follow a unidirectional manner.
O2P-H1Ø Nicotine and morphine interactions; new protocol for morphine dependency in mice Abbas Khani, Abbas Haghparast, Nima Naderi, Amir-Mohammad Alizadeh, Fereshteh Motamedi Neuroscience Research Center, Shaheed Beheshti Medical University, Tehran, Iran Clinical use of morphine in pain management is controversial. Both nicotine and morphine are widely abused. We investigated the influence of nicotine on the development of morphine tolerance and dependence. Along with concurrent nicotine administration, 160 male mice were rendered dependent on morphine according both the method previously described by Marshall and Smith–Grahame (M groups) and 50% doses of morphine in the method (M50 groups). Tail flick latency before and after morphine injection and withdrawal Jumping test were used for the assessment of tolerance and dependency, respectively. We found: first, 50% doses of morphine in Marshall method is sufficient to induce dependency but not tolerance in mice; second, nicotine attenuates the development of tolerance in dose-dependent manner in M groups and significantly decreases withdrawal jumping in both M and M50 groups in a biphasic profile (V-shape) manner.
O2P-HØ2 IL-1 receptor antagonist (IL-1Ra) KO mice show
S65
O2P-HØ7 Identification of YWHAE, a gene encoding 14-3-3,
anxiety-like behavior
as a novel susceptibility gene for schizophrenia
Chisato Wakabayashi 1,2 , Yoichiro Iwakura 1 1 Laboratory of Cell Biology, University of Tokyo, Tokyo, Japan; 2 Japan Society for the Promotion of Science (JSPS), Tokyo, Japan
Takao Hikita 1 , Masashi Ikeda 2 , Shinichiro Taya 1 , Takeshi Miyakawa 3 , Kozo Kaibuchi 1 , Norio Ozaki 4 , Nakao Iwata 2 1 Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya, Japan; 2 Department of Psychiatry, Fujita Health University, Toyoake, Japan; 3 Department of Genetic Engineering and Functional Genomics, Kyoto University, Kyoto, Japan; 4 Department of Psychiatry, Nagoya University, Nagoya, Japan
It is well known that the expression of IL-1 mRNA is induced by stress. Lines of evidence show that IL-1 administration influences the release of monoamines and these effects are attenuated by the pre-administration of IL-1Ra. These results strongly suggest that IL-1 directly influences monoamine contents in the brain and trigger the mental disease, such as anxiety and depression. It is unclear, however, the precise roles of IL-1 in the development of psychological diseases. In this study, we used the IL-1Ra KO mice and examined various behavioral tests. Because of the absence of IL-1Ra, physiological levels of IL-1 in the brain may activate the receptor excessively resulting in the similar situation as stressed animals. Very interestingly, at 20 weeks, anxiety-like behavior was appeared and was ameliorated by the administration of Diazepam. Further mechanisms of the induction pathways are now fully investigating. Research funds: Grant-in-Aid for JSPS Fellows
Disrupted-In-Schizophrenia 1 (DISC1) is one of the candidate genes for the susceptibility to schizophrenia. We investigated the genetic association between DISC1 interacting molecules and schizophrenia in a Japanese population, and identified a promoter SNP for YWHAE, a gene encoding 14-3-3. The minor allele frequencies of this SNP were higher in controls. mRNA transcription and protein expression of 14-3-3 were increased in the lymphocytes of healthy control subjects harboring heterozygous and homozygous minor allele. Ywhae+/− mice showed cognitive dysfunctions that are observed in schizophrenia patients. These results suggest that YWHAE is a novel susceptibility gene to schizophrenia that works protectively. Research funds: KAKENHI 15GS0319, KAKENHI 17024024, 21st Century Centre of Excellence Program
O2P-HØ4 Chronic effects of methamphetamine, MDMA and 5-MeO-DiPT on raphe serotonergic neurons in rat organotypic mesencephalic slice culture Megumi Higuchi, Yuichi Suzuki, Takayuki Nakagawa, Shuji Kaneko Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan Recent evidence suggests the involvement of raphe serotonergic neurons in drug dependence and addiction to the psychostimulant, methamphetamine (METH), and recreational drugs such as 3,4methylenedioxymethamphetamine (MDMA) or 5-MeO-DiPT. In this study, we examined the chronic effects of METH, MDMA and 5-MeO-DiPT on serotonin release and serotonergic neurotoxicity in rat organotypic mesencephalic slice cultures containing the raphe nuclei. Acute treatment with METH and MDMA dose-dependently increased serotonin release, while 5-MeO-DiPT did not. Sustained treatment with METH or MDMA for 6 days followed by their challenge (24 h later) significantly augmented their serotonin-releasing effects. Sustained treatments with 5-MeO-DiPT decreased tissue contents of serotonin and [3 H]citalopram binding, while METH and MDMA had little effect. These results suggest that chronic treatment with METH or MDMA induces serotonergic sensitization, while 5-MeO-DiPT produces serotonergic neurotoxicity without serotonin release.
O2P-HØ5 Regulation of DISC1 through phosphorylation by ERK Shinichiro Taya, Junko Uraguchi-Asaki, Keisuke Kuroda, Kozo Kaibuchi Department of Cell Pharmacology, Nagoya University, Nagoya, Japan Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. Previously, we reported that Kinesin-1, a motor protein of anterograde axonal transport, as a novel DISC1-interacting protein. Kinesin-1 interacts with the NUDEL/LIS1/14-3-3epsilon complex or Grb2 through DISC1. The knockdown of DISC1 inhibits the accumulation of the NUDEL complex and Grb2 at the axons and axon elongation. DISC1 appears to regulate the localization of the NUDEL complex and Grb2 into the axons as a cargo receptor for axon elongation. However, it remains unknown how the functions of DISC1 are regulated. Here, we found that the phosphorylation of DISC1 was increased by treatment with a phosphatase inhibitor, Calyculin A, and this phosphorylation was canceled by treatment with an ERK inhibitor. DISC1 was directly phosphorylated by ERK in a cell-free system. The physiological meanings of DISC1 phosphorylation by ERK will be discussed. Research funds: KAKENHI (18700363) (17024024) (15GS0319)
O2P-HØ9 Chronic administration of nicotine retards the development of morphine dependency and tolerance in mice Abbas Haghparast, Nima Naderi, Abbas Khani, Amir Alizadeh, Fereshteh Motamedi Neuroscience Research Center, Shaheed Beheshti Medical University, Tehran, Iran Investigating the interaction between nicotinic and opioid receptors is of great interest to both basic mechanistic and clinical views. Eighty male mice were rendered dependent on morphine. We used repeated injection of nicotine (0.001, 0.01, 0.1, 1 and 2 mg/kg; ip) 15 min prior to each morphine application along with control groups. Tail Flick latency pre- and post-morphine injection and number of jumping after injection of naloxone (5 mg/kg; ip), 2 h after morphine application in the fourth day, were used as indexes for development of tolerance and dependency, respectively. Results showed that nicotine doses at 2, 1 and 0.1 mg/kg significantly reversed the development of tolerance. The most effective dose of nicotine that significantly decreased the number of jumping is 0.1 mg/kg. So, our study indicates that repeated injection of nicotine reverses the development of morphine tolerance and dependency. Dose–response curve of nicotine vs. decrease in development of morphine dependency interestingly does not follow a unidirectional manner.
O2P-H1Ø Nicotine and morphine interactions; new protocol for morphine dependency in mice Abbas Khani, Abbas Haghparast, Nima Naderi, Amir-Mohammad Alizadeh, Fereshteh Motamedi Neuroscience Research Center, Shaheed Beheshti Medical University, Tehran, Iran Clinical use of morphine in pain management is controversial. Both nicotine and morphine are widely abused. We investigated the influence of nicotine on the development of morphine tolerance and dependence. Along with concurrent nicotine administration, 160 male mice were rendered dependent on morphine according both the method previously described by Marshall and Smith–Grahame (M groups) and 50% doses of morphine in the method (M50 groups). Tail flick latency before and after morphine injection and withdrawal Jumping test were used for the assessment of tolerance and dependency, respectively. We found: first, 50% doses of morphine in Marshall method is sufficient to induce dependency but not tolerance in mice; second, nicotine attenuates the development of tolerance in dose-dependent manner in M groups and significantly decreases withdrawal jumping in both M and M50 groups in a biphasic profile (V-shape) manner.