1.Faculty Member/Staff
Department of Neuropsychopharmacology (2009.02.01)
Professor:
Kiyofumi Yamada, Ph.D.
Associate Professor:
Atsumi Nitta, Ph.D.
Designated Lecturer:
Taku Nagai, Ph.D.
Designated Assistant Professor:
Erika Toth, Ph.D. (supported by G-COE, from Israel)
Research Resident:
Yoko Hibi, Ph.D. (supported by Japan Foundation for Aging and Health)
Foreign Researcher:
Jinghua Yu, Ph.D. (supported by Frontier Science at Meij Univ., from China)
Wenting Liu, Ph.D. (from China)
Graduate Student:
Daisuke Ibi (D-3)
Jaesuk Yun (D-1, from South Korea)
Hiroyuki Koike (MS-2)
Yuko Kitahara (MS-1)
Eiichi Someya (MS-1)
Adult Graduate Student:
Yasuhiro Miyagawa (D-4)
Yoshiaki Kato (D-3)
Masayuki Miyazaki (D-3)
Yasuo Kumakura (D-1)
Hideyuki Kushihara (D-1)
Akira Yoshimi (D-1)
Special Research Student:
Hiroyuki Koike (MS-2, Kanazawa Univ.)
Takenao Kozeki (MS-2, Meijo Univ.)
Visiting Professor:
Yukihiro Noda, Ph.D. (Meijo Univ.)
Visiting Researcher:
Hiroyuki Kamei, Ph.D. (Meijo Univ.)
Takayoshi Mamiya , Ph.D. (Meijo Univ.)
Hiroyuki Mizoguchi, Ph.D. (Res. Inst. Environ. Med., Nagoya Univ.)
Makoto Mizuno, Ph.D. (Niigata Univ.)
Akihiro Mouri, Ph.D. (Meijo Univ.)
Makoto Nakao, Ph.D. (Kinjo Univ.)
Minae Niwa, Ph.D. (Meijo Univ.)
Takashi Osada, Ph.D. (Aichi Gakuin Univ.)
Manabu Tanimura (Yamada Red Cross Hosp.)
Keiko Yamamura, Ph.D. (Aichi Gakuin Univ.)
Department of Hospital Pharmacy (2009.02.01)
Director:
Kiyofumi Yamada, Ph.D.
Vice Director:
Atsumi Nitta, Ph.D.
Takafumi Kuzuya, Ph.D.
Akio Itoh, Ph.D.
Isao Muraoka, Ph.D.
Chief Pharmacist:
Motonori Ohshima
Masahiko Shinoda, Ph.D.
Masaya Hasegawa, Ph.D.
Noriko Tamaoki
Saori Ohta
Masato Yamamoto, MSc.
Katsuyoshi Kato
Masayuki Umemura, Ph.D.
Koji Yano, Ph.D., BCNSP
Kumiko Shimizu, CCRC
Koji Senzaki
Satoko Tezuka, MSc.
Pharmacist:
Mayumi Torimoto, MSc.
Masako Ishizuka
Yasuhiro Miyagawa, MSc.
Masayuki Miyazaki, MSc.
Yasuo Kumakura, MSc.
Yusuke Sakai, MSc.
Aki Kubota, MSc., CDEJ
Mie Tsuji
Yoshiaki Kato, MSc.
Tomoko Matsugaki, MSc.
Noriko Kiriyama, MSc.
Mako Okabe
Yosuke Niwa, MSc.
Yoko Morita
Yoko Ishiguro
Etsuko Ito, MSc.
Yasuko Nakao
Mako Ito
Akira Yoshimi, MSc.
Hiroshi Kato, MSc.
Sumiyo Kondo, MSc.
Kaori Kobayashi, MSc.
Michie Ito
Kyoko Suzuki
Mika Ohara
Chikako Yamada
Motoki Sano
Noriko Izawa
Chiyo Yamamoto
Sakiko Miyakawa
Technician:
Yuriko Nakayama
Administrator:
Fusako Hayakawa (Chief)
Yuko Marumo
Kikuko Yogo
2.Introduction of Research
Department of Neuropsychopharmacology
The brain controls all body activities, ranging from heart rate to memory. Each brain function is operated by particular neural circuits made by synapses. The most important feature of synapses is the activity-dependent plasticity. The long-term objective in our laboratory is twofold. One is to define the molecular and cellular mechanisms that regulate synaptic plasticity associated with learning and memory. In particular, we are interested in molecular and cellular mechanisms that are responsible for working/short-term memory and reference/long-term memory. The other is to define the pathogenesis/pathophysiology of neuropsychiatric brain disorders, including Alzheimer’s disease, schizophrenia and drug addiction. Our current efforts have been focused on the following projects.
(1)Schizophrenia and other mental disorders
Both genetic and environmental factors play a role in the pathology of schizophrenia. Recently, genetic susceptibility factors for the disorder have become available, which include neuregulin-1, dysbindin, and disrupted-in-schizophrenia 1 (DISC1). Epidemiological studies have identified environmental factors for schizophrenia, and maternal viral infection during pregnancy is regarded as the most promising one. Viral infection in the second trimester of pregnancy in humans increases the risk of subsequently developing schizophrenia in adolescence/adulthood. A possible interaction between environmental and genetic susceptibility factors, especially during neurodevelopment, is proposed for the disease etiology.
We focus on phenotypic analyses at behavioral, neurochemical and neuroanatomical levels in mice with mutant schizophrenia susceptibility genes such as DISC1. We also study a possible interaction of genetic and environmental factors in schizophrenia by using a genetically-engineered mouse models under exposure to the synthetic double strand RNA polyriboinosinic-polyribocytidilic acid [polyI:C, a toll-like receptor 3 (TLR3) ligand that induces strong innate immune response]. PolyI:C has been used to mimic a viral infection during neurodevelopment for modeling schizophrenia in mice.
(2)Alzheimer’s disease and other neurodegenerative disorders
Alzheimer’s disease (AD) is a progressive neurodegenerative process characterized by senile plaques, neurofibrillary tangles and neuronal loss. A pathologic hallmark of AD is deposition of amyloid-? peptide (A?), a 39-43-amino acid peptide derived from the transmembrane amyloid precursor protein (APP). Fibrillar A? deposits are found in extracellular senile plaque cores and are associated with neurodegeneration in later stages of AD. We study the mechanisms underlying the A?-induced neurotoxicity in vivo, by directly injecting A? into the lateral ventricle. We have already discoverd novel compounds to prevent the A?-induced neurotoxicity.
(3)Drug addiction/dependence
Drug addiction/dependence is defined as a chronically relapsing disorder that is characterized by compulsive drug taking, inability to limit intake, and intense drug cravings. The positive reinforcing/rewarding effects of drugs primarily depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens while the craving for drugs is associated with activation of the prefrontal cortex. The chronic intake of drugs causes homeostatic molecular and functional changes in synapses, which may be critically associated with the development of drug dependence. We have demonstrated that various cytokines such as TNF-? and GDNF and proteinases such as tissue plasminogen activator (tPA) and matrix metalloproteinase (MMP-2/MMP-9) are produced in the brain on treatment with drugs of abuse, and play a role in drug dependence. These endogenous modulators of drug dependence are classified into two groups, pro-addictive and anti-addictive factors. We have proposed that an imbalance between pro-addictive and anti-addictive factors contributes to the development and relapse of drug dependence. Targeting these endogenous modulators would provide new therapeutic approaches to the treatment of drug dependence.
(4)Basic mechanisms of learning/memory and emotion
Recognition memory is a fundamental facet of ability to remember, and an integral component of the class of memory lost in amnesia. The ability to discriminate familiar from novel stimuli is supported by this form of memory and is widely used as an assay in animals. Recent work highlights a major role in recognition memory for the perirhinal cortex because lesions or transient inactivation of perirhinal cortex consistently disrupt performance on familiarity discrimination tasks with object in both primates and rats.
We have previously demonstrated that the activation of ERK1/2 following stimulation of dopamine D1 receptors in the prefrontal cortex is necessary for the protein synthesis-dependent long-term retention of recognition memory. Now, we focus on the possible interaction between dopamine and glutamate systems in protein synthesis-dependent long-term retention of recognition memory. Furthermore, we look for target genes of the dopamine D1 receptor-ERK1/2 signaling which are responsible for long-term recognition memory.
Department of Hospital Pharmacy
We conduct clinical researches in collaboration with clinical departments at Nagoya University Hospital. These studies include the effect of pharmaceutical care by pharmacists on patient’s QOL, pharmacokinetics of immunesuppressants, pharmacotherapy and side effects, and pharmacogenetics.
3.Representative publications (2000- )
Department of Neuropsychopharmacology
(1) Schizophrenia and other mental disorders
- Miyamato Y, Yamada K, Noda Y, Mori H, Mishina M and Nabeshima T: Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking NMDA receptor ?1 subunit. J. Neurosci. 21, 750-757, 2001.
- Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M and Nabeshima T: Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor ?4 subunit. J. Neurosci. 22, 2335-2342, 2002
- Jin D, Liu HX, Hirai H, Torashima T, Nagai T, Lopatina O, Shnayder NA, Yamada K, Noda M, Seike T, Fujita K, Takasawa S, Yokoyama S, Koizumi K, Shiraishi Y, Tanaka S, Hashii M, Yoshihara T, Higashida K, Islam MS, Yamada N, Hayashi K, Noguchi N, Kato I, Okamoto H, Matsushima A, Salmina A, Munesue T, Shimizu N, Mochida S, Asano M and Higashida H: CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446, 41-45, 2007.
- Ibi D, Takuma K, Koike H, Mizoguchi H, Tsuritani K, Kuwahara Y, Kamei H, Nagai T, Yoneda Y, Nabeshima T and Yamada K: Social isolation rearing-induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion-related behaviors in juvenile mice. J. Neurochem. 105, 921-932, 2008.
(2)Alzheimer’s disease and other neurodegenerative disorders
- Iida R, Saito K, Yamada K, Basile AS, Sekikawa K, Takemura M, Fujii H, Wada H, Seishima M and Nabeshima T: Suppression of neurocognitive damage in LP-BM5 infected mice with a targeted deletion of the TNF-? gene. FASEB J. 14, 1023-1031, 2000.
- Tran MH, Yamada K, Olariu A, Mizuno M, Ren XH and Nabeshima T: Amyloid ?-peptide induces nitric oxide production in rat hippocampus: association with cholinergic dysfunction and amelioration by inducible nitric oxide synthase inhibitors. FASEB. J. 15, 1407-1409, 2001.
- Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, Nabeshima Y and Nabeshima T: Cognition impairment in the genetic model of aging, klotho gene mutant mice: a role of oxidative stress. FASEB J. 17, 50-52, 2003.
- Tran MH, Yamada K, Nakajima A, Mizuno M, He J, Kamei H and Nabeshima T: Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid ?-peptide-induced cholinergic dysfunction. Mol. Psychiatry 8, 407-412, 2003.
- Takuma K, Matsuo A, Himeno Y, Hoshina Y, Ohno Y, Funatsu Y, Arai S, Kamei H, Mizoguchi H, Nagai T, Koike K, Inoue M and Yamada K: 17?-Estradiol attenuates hippocampal neuronal loss and cognitive dysfunction induced by chronic restraint stress in ovariectomized rats. Neuroscience 146, 60-68, 2007.
- Alkam T, Nitta A, Mizoguchi H, Itoh A, Murai R, Nagai T, Yamada K and Nabeshima T: The extensive nitration of neurofilament light chain in the hippocampus is associated with the cognitive impairment induced by amyloid ? in mice. J. Pharmacol. Exp. Ther. 327, 137-147, 2008.
(3) Drug addiction/dependence
- Miyamoto Y, Yamada K, Nagai T, Mori, H, Mishina M, Furukawa H, Noda Y and Nabeshima T: Behavioral adaptations to addictive drugs in mice lacking NMDA receptor ?1 subunit. Eur. J. Neurosci. 19, 151-158, 2004.
- Nakajima A, Yamada K, Nagai T, Uchiyama T, Miyamoto Y, Mamiya T, Nitta A, Mizuno M, Tran MH, Seto A, Yoshimura M, Kitaichi K, Hasegawa T, Saito K, Yamada Y, Seishima M, Sekikawa K, Kim HC and Nabeshima T: Role of TNF-? in methamphetamine-induced drug dependence and neurotocicity. J. Neurosci. 24, 2212-2225, 2004.
- Nagai T, Yamada K, Yoshimura M, Ishikawa K, Miyamoto M, Hashimoto K, Noda Y, Nitta A and Nabeshima T: Tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release. Proc. Natl. Acad. Sci. U.S.A. 101, 3650-3655, 2004.
- Mizoguchi H, Yamada K, Mizuno M, Mizuno T, Noda Y, Nitta A and Nabeshima T: Regulation of methamphetamine reward by extracellualr signal-regulated kinase 1/2/ets-like gene-1 signaling pathway via the activation of dopamine receptors. Mol. Pharmacol. 65, 1293-1301, 2004.
- Kamei H, Nagai T, Nakano H, Togan Y, Takayanagi M, Takahashi K, Kobayashi K, Yoshida S, Maeda K, Takuma K, Nabeshima T and Yamada K: Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK 1/2 activation in the prefrontal cortex. Biol. Psychiatry 59, 75-84, 2006.
- Nagai T, Ito M, Nakamichi N, Mizoguchi H, Kamei H, Fukakusa A, Nabeshima T, Takuma K and Yamada K: The rewards of nicotine: regulation by tissue plasminogen activator-plasmin system through protease activated receptor-1. J. Neurosci., 26, 12374-12383, 2006.
- Mizoguchi H, Yamada K, Niwa M, Mouri A, Mizuno T, Noda Y, Nitta A, Itohara S, Banno Y and Nabeshima T: Reduction of methamphetamine-induced sensitization and reward in matrix metalloproteinase-2 and -9 deficient mice. J. Neurochem. 100, 1579-1588, 2007.
- Yan Y, Yamada K, Niwa M, Nagai T, Nitta A and Nabeshima T: Enduring vulnerability to reinstatement of methamphetamine-seeking behavior in glial cell line-derived neurotrophic factor mutant mice. FASEB J. 21, 1994-2004, 2007.
- Arai S, Takuma K, Mizoguchi H, Ibi D, Nagai T, Takahashi K, Kamei H, Nabeshima T and Yamada K: Involvement of pallidotegmental neurons in methamphetamine- and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice: reversal by GABAB receptor agonist baclofen. Neuropsychopharmacology 33, 3164-3175, 2008.
(4) Basic mechanisms of learning/memory and emotion
- Mizuno M, Yamada K, Olariu A, Nawa H and Nabeshima T: Involvement of BDNF in spatial memory formation and maintenance in a radial arm maze test in rats. J. Neurosci. 20, 7116-7121, 2000.
- He J, Yamada K and Nabeshima T: A role of Fos expression in the CA3 region of the hippocampus in spatial memory formation in rats. Neuropsychopharmacology 26, 259-268, 2002.
- Mizuno M, Yamada K, Takei N, Tran MH, He J, Nakajima A, Nawa H and Nabeshima T: Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation. Mol. Psychiat. 8, 217-224, 2003.
- Mizuno M, Yamada K, He J, Nakajima A and Nabeshima T: Involvement of BDNF receptor TrkB in spatial memory formation. Learn. Mem. 10, 108-115, 2003.
- Ito M, Nagai T, Kamei H, Nakamichi N, Nabeshima T, Takuma K and Yamada K: Involvement of tissue plasminogen activator-plasmin system in depolarization-evoked dopamine release in the nucleus accumbens of mice. Mol. Pharmacol. 70, 1720-1725, 2006.
- Takahashi K, Nagai T, Kamei H, Maeda K, Matsuya T, Arai S, Mizoguchi H, Yoneda Y, Nabeshima T, Takuma K and Yamada K: Neural circuits containing pallidotegmental GABAergic neurons are involved in the prepulse inhibition of the startle reflex in mice. Biol. Psychiatry 62, 148-157, 2007.
- Nagai T, Takuma K, Kamei H, Ito Y, Nakamichi N, Ibi D, Nakanishi Y, Murai M, Mizoguchi H, Nabeshima T and Yamada K: Dopamine D1 receptors regulate protein synthesis-dependent long-term recognition memory via extracellular signal-regulated kinase 1/2 in the prefrontal cortex. Learn Mem. 14, 117-125, 2007.
Department of Hospital Pharmacy
- Maruyama T, Sugiura S, Kojima J, Arimasa Y, Satoh Y, Kanaji K, Matsumura T, Ohsumi K, Yamada K and Nabeshima T: Improvement in drug compliance by medical consultation at a pharmacist outpatients’ clinic (Part 1). J. Appl. Therapeut. Res. 4, 18-24, 2003.
- Kuzuya, T., Kobayashi, T., Moriyama, N., Nagasaka, T., Yokoyama, I., Uchida, K., Nakao, A. and Nabeshima, T.: Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients. Transplantation 76, 865-868, 2003.
- Ishikawa, K., Kajita, Y., Hasegawa, Y., Noda, Y., Yoshida, J. and Nabeshima, T.: Irinotecan therapy in a 12-year-old girl with recurrent brain stem glioma and without functional polymorphisms in UGT1A1 activity: case report. J. Neurooncol. 74, 283-286, 2005.
- Hasegawa, M., Takagi, K., Shimosaka, K., Byrd, H.J. and Nabeshima, T.: Evaluation of “Bronchial Asthma Pharmaceutical Care Clinic for Outpatients” run by pharmacists at Nagoya University Hospital. Jpn. J. Pharm. Health Care Sci. 32, 1038-1043 (2006）
- Yoshida M, Morita R, Lefor AT and Nabeshima T: Implementation and evaluation of a once daily amikacin dosing protocol in a long-term care facility. Int. J. Antimicrob. Agents 29, 113-116, 2007.
- Amioka K, Kuzuya T, Kushihara H, Ejiri M, Nitta A and Nabeshima T: Carvedilol increases ciclosporin bioavailability by inhibiting P-glycoprotein-mediated transport. J. Pharm. Pharmacol. 59, 1383-1387, 2007.
- Umegaki H, Itoh A, Suzuki Y and Nabeshima T: Discontinuation of donepezil for the treatment of Alzheimer's disease in geriatric practice. Int. Psychogeriatr. 20, 800-806, 2008.
- Yano K, Yamamura K, Osada T, Fukase F, Kiriyama N, Torimoto M, Yamada K, Kishi DT and Nabeshima T: Documenting the value of a pharmacist-managed anticoagulation classroom. J. Appl. Ther. Res. 6, 41-48, 2008.
- Yamamoto, Kuzuya, Yamada K and Nabeshima T: Population pharmacokinetic analysis of vancomycin in patients with gram-positive infections and the influence of infectious disease type. J. Clin. Pharm. Ther., in press.
Department of Neuropsychopharmacology & Hospital Pharmacy
Nagoya University Graduate School of Medicine
65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan
Tel : +81-52-744-2674, Fax : +81-52-744-2979
E-mail : pharmacy@med.nagoya-u.ac.jp