INVESTIGATION OF THE NEUROCHEMICAL MECHANISM UNDERLYING DRUG ADDICTION USING IN VIVO PET IMAGING

• Project/Area Number: 16591178
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: NATIONAL INSTITUTE OF RADIOLOGICAL SCIENCES
• Principal Investigator: OBAYASHI SHIGERU NATIONAL INSTITUTE OF RADIOLOGICAL SCIENCES, DEPT. MOLECULAR NEUROIMAGING, MOLECULAR IMAGING CENTER, TEAM LEADER, 分子イメージング研究センター分子神経イメージング研究グループ, チームリーダー (90318246)
• Co-Investigator(Kenkyū-buntansha): SUHARA TETSUYA NATIONAL INSTITUTE OF RADIOLOGICAL SCIENCES, MOLECULAR NEUROIMAGING, GROUP LEADER, 分子イメージング研究センター分子神経イメージング研究グループ, グループリーダー (90216490)
• Project Period (FY): 2004 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: positron emission tomography(PET) / macaque monkeys / drug addiction / plasticity / dopamine / マイクロダイアリシス法

Research Abstract

In this research project, we sought to explore the neurochemical mechanism underlying drug addiction using in vivo positron emission tomography (PET) with awake monkeys in combination with some invasive techniques. In the first year, we used microdialysis technique to investigate the neurochemical changes in the ventral striatum such as necleus accumbense by repetitive metamphetamine administration. The preliminary study suggested that the increase in methamphetamine-induced extracellular dopamine release would be augmented exponentially every methamphetamine exposure. In the second year, we investigated the long-term changes in the dopamine system caused by chronic exposure to the above addictive drug in an awake treated monkey using PET with [^<11>C]NNC112 and [^<11>C]FLB457. Our preliminary data suggested that the dopamine D1 receptor availability quantified by PET measurement with [^<11>C]NNC112 was decreased in PFC, whereas the dopamine D2 availability quantified by PET measurement with [^<11>C]FLB457 was increased in thalamus. In the last year, unfortunately, due to an accident bitten by monkey, we are forced to interrupt all of our monkey studies in our institute for 8 months till our study with monkeys was restarted. Meanwhile, we developed a intra-venous self-administration system for monkeys that could quantify the values of craving for the drug by counting lever responses. We are now training the task where monkeys can get food rewards or experience cocaine exposure when reaching a criteria by pressing a lever in front of the abdomen. The monkeys can recognize by visual cues which one of reward monkeys would be avialable. We expect that we can detect the neural basis underlying craving for cocaine by contrasting between regional CBF measured by PET with 0-15 labeled water during food reward condition and cocaine condition in the near future.

Research Products

• [Journal Article] In vivo mapping of substance P receptors in brains of laboratory animals by high-resolution imaging systems (2007)
  • Author(s): E.Haneda, M.Higuchi, J.Maeda, M.Inaji, T.Okauchi, K.Ando, S.Obayashi, Y.Nagai, M.Narazaki, H.Ikehira, T.Nakao, M.R.Zhangl, K.Suzuki, H.Suzuki, T.Suhara
  • Journal Title: Synapse 61(4) Pages: 205-515
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional organization of monkey brain for abstract operation (2007)
  • Author(s): S.Obayashi, R.Matsumoto, T.Suhara, Y.Nagai, J.Maeda, T.Okauchi, A.Iriki
  • Journal Title: Cortex 3 Pages: 389-396
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional organization of monkey brain for abstract operation (2007)
  • Author(s): S.Obayashi, R.Matsumoto, T.Suhara, Y.Nagai, J.Maeda, T.Okauchi, A.Iriki.
  • Journal Title: Cortex 43 Pages: 389-396
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] In vivo mapping of substance P receptors in brains of laboratory animals by high-resolution imaging systems (2007)
  • Author(s): E.Haneda, M.Higuchi, J.Maeda, M.Inaji, T.Okauchi, K.Ando, S.Obayashi, Y.Nagai, M.Narazaki, H.Ikehira, T.Nakao, M.R.Zhangl, K.Suzuki, H.Suzuki, T.Suhara
  • Journal Title: Synapse 61(4): Pages: 205-515
• [Journal Article] Functional organization of monkey brain for abstract operation (2007)
  • Author(s): S.Obayashi, R Matsumoto, T.Suhara, Y.Nagai, J.Maeda, T.Okauchi, A.Iriki.
  • Journal Title: Cortex 3 Pages: 389-396
• [Journal Article] Extension of corticocortical afferents into the anterior bank of the intraparietal sulcus by tool-use training in adult monkeys (2006)
  • Author(s): Hihara, S., Notoya, T., Tanaka, M., Ichinose, S., Ojima, H., Obayashi, S., Fujii, N., Iriki, A.
  • Journal Title: Neuropsychologia 44(3) Pages: 2636-2646
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] In vivo evaluation of P-glycoprotein function at the blood-brain barrier in nonhuman primates using [11C]verapamil. (2006)
  • Author(s): Lee, Y.J., Maeda, J., Kusuhara, H., Okauchi, T., Inaji, M., Nagai, Y., Obayashi, S., Nakao, R., Suzuki, K., Sugiyama, Y., Suhara, T.
  • Journal Title: J Pharmacol Exp Ther. 316(2) Pages: 647-653
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Extension of corticocortical afferents into the anterior bank of the intraparietal sulcus by tool-use training in adult monkeys (2006)
  • Author(s): Hihara, S, Notoya, T, Tanaka, M, Ichinose, S, Ojima, H, Obayashi, S, Fujii, N, Iriki, A.
  • Journal Title: Neuropsychologia 44(3) Pages: 2636-2646
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] In vivo evaluation of P-glycoprotein function at the blood-brain barrier in nonhuman primates using [11C]verapamil. (2006)
  • Author(s): Lee, Y.J, Maeda, J, Kusuhara, H, Okauchi, T, Inaji, M, Nagai, Y, Obayashi, S, Nakao, R, Suzuki, K, Sugiyama, Y, Suhara, T.
  • Journal Title: J Pharmacol Exp Then 316(2) Pages: 647-653
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Extension of corticocortical afferents into the anterior bank of the intraparietal sulcus by tool-use training in adult monkeys (2006)
  • Author(s): Hihara, S, Notoya, T., Tanaka, M, Ichinose, S., Ojima H., Obayashi, S., Fujii, N., Iriki, A.
  • Journal Title: Neuropsychologia 44(3) Pages: 2636-2646
• [Journal Article] Functional organization of monkey brain for abstract operation (2006)
  • Author(s): Obayashi S, Matsumoto R, Suhara T, Nagai Y, Maeda J, Okauchi T, Iriki.A.
  • Journal Title: Cortex (In press)
• [Journal Article] Extension of corticocortical afferents into the anterior bank of the intraparietal sulcus by tool-use training in adult monkeys (2006)
  • Author(s): Hihara, S., Notoya, T., Tanaka, M., Ichinose, S., Ojima, H., Obayashi, S., Fujii, N., Iriki, A.
  • Journal Title: Neuropsychologia (In press)
• [Journal Article] Correlation between quantitative imaging and behavior in unilaterally 6-OHDA-lesioned rats (2005)
  • Author(s): Inaji, M., Okauchi, T., Ando K., Maeda, J., Nagai, Y., Yoshizaki, T., Okano, H., Nariai, T., Ohno, K., Obayashi, S., Higuchi, M., Suhara, T.
  • Journal Title: Brain Res. 1064(1-2) Pages: 136-145
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] In Vivo PET measurements with [11C]PE2I to evaluate fetal masencephalic transplantations to unilateral 6-OHDA-lesioned rats (2005)
  • Author(s): Inaji, M., Yoshizaki, T., Okauchi, T., Maeda, J., Nagai, Y., Nariai, T., Ohno, K., Ando, K., Okano, H., Obayashi, S., Suhara, T.
  • Journal Title: Cell Transplantation 14(9) Pages: 655-663
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Correlation between quantitative imaging and behavior in unilaterally 6-OHDA-lesioned rats (2005)
  • Author(s): Inaji, M, Okauchi, T, Ando K, Maeda, J, Nagai, Y, Yoshizaki, T, Okano, H, Nariai, T, Ohno, K, Obayashi, S, Higuchi, M, Suhara, T.
  • Journal Title: Brain Res. 1064(1-2) Pages: 136-145
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] In Vivo PET measurements with [11C]PE2I to evaluate fetal masencephalic transplantations to unilateral 6-OHDA-lesioned rats (2005)
  • Author(s): Inaji, M, Yoshizaki, T, Okauchi, T, Maeda, J, Nagai, Y, Nariai, T, Ohno, K, Ando, K, Okano, H, Obayashi, S, Suhara, T.
  • Journal Title: Cell Transplantation 14(9) Pages: 655-663
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Monkey brain areas underlying remote-controlled operation. (2004)
  • Author(s): Obayashi S., Suhara T., Nagai Y., Okauchi T., Maeda J., Iriki A.
  • Journal Title: Eur J Neurosci. 19 Pages: 1397-1407
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Relationship between cortical dopamine D_2 receptor occupancy and suppression of conditioned avoidance response in non-human primate. (2004)
  • Author(s): Takano A., Suhara T., Maeda J., Ando K., Okauchi T., Obayashi S.
  • Journal Title: Psychiatry Clin. Neurosci. 58 Pages: 330-332
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Novel peripheral benzodiazepine receptor ligand [^<11>C]DAA1106 for PET : an imaging tool for glial cells in the brain. (2004)
  • Author(s): Maeda J., Suhara T., Zhang M.-R., Okauchi T., Yasuno F., Ikoma Y.
  • Journal Title: Synapse 52 Pages: 283-291
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Development of a new radioligand, N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[^<18>F]fluoroethyl-5-methoxybenzyl (2004)
  • Author(s): Zhang M.-R., Maeda J., Ogawa M., Noguchi J., Ito T., Yoshida Y.
  • Journal Title: J Med. Chem. 47 Pages: 2228-2235
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Monkey brain areas underlying remote-controlled operation (2004)
  • Author(s): Obayashi S., Suhara T., Nagai Y., Okauchi T., Maeda J., Iriki A.
  • Journal Title: Eur J Neurosci. 19 Pages: 1397-1407
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Relationship between cortical dopamine D2 receptor occupancy and suppression of conditioned avoidance response in non-human primate. (2004)
  • Author(s): Takano A., Suhara T., Maeda J., Ando K., Okauchi T., Obayashi S., T.Nakayama, S.Kapur.
  • Journal Title: Psychiatry Clin. Neurosci. 58 Pages: 330-332
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Novel peripheral benzodiazepine receptor ligand [11C]DAA1106 for PET : an imaging tool for glial cells in the brain. (2004)
  • Author(s): Maeda J., Suhara T., Zhang M.-R., Okauchi T., Yasuno F., Ikoma Y., Inagi M., Nagai Y., Takano A., Obayashi S., Suzuki K.
  • Journal Title: Synapse 52 Pages: 283-291
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Development of a new radioligand, N-(5-Fluoro-2-phenoxypheny1)-N-(2-[18F]fluoroethyl-5-methoxybenzyl )acetamide, for PET imaging of peripheral benzodiazepine receptor in primate brain. (2004)
  • Author(s): Zhang M.-R., Maeda J., Ogawa M., Noguchi J., Ito T., Yoshida Y., Okauchi T., Obayashi S., Suhara T., Suzuki K.
  • Journal Title: J Med. Chem. 47 Pages: 2228-2235
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Relationship between cortical dopamine D_2 receptor occupancy and suppression of conditioned avoidance response in non-human primate. (2004)
  • Author(s): Takano A., Suhara T., Maeda J., Ando K., Okauchi T., Obayashi S., Nakayama T., Kapur S.
  • Journal Title: Psychiatry Clin.Neurosci. 58 Pages: 330-332
• [Journal Article] Novel peripheral benzodiazepine receptor ligand [^<11>C]DAA1106 for PET : an imaging tool for glial cells in brain. (2004)
  • Author(s): Maeda J., Suhara T., Zhang M.-R., Okauchi T., Yasuno F., Ikoma Y., Inagi M., Nagai Y., Takano A., Obayashi S., Suzuki K.
  • Journal Title: Synapse 52 Pages: 283-291
• [Journal Article] Development of a new radioligand, N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[^<18>F]fluoroethyl-5-methoxybenzyl)acetamide, for PET imaging of peripheral benzodiazepine receptor primate brain. (2004)
  • Author(s): Zhang M.-R., Maeda J., Ogawa M., Noguchi J., Ito T., Yoshida Y., Okauchi T., Obayashi S., Suhara T., Suzuki K.
  • Journal Title: J Med.Chem. 47,2004 Pages: 2228-2235
• [Journal Article] In vivo Brain Imaging of Progressive Striatal Degeneration in MPTP-treated monkeys using PET with multiple tracers
  • Author(s): Y.Nagai, S.Obayashi, K.i Ando, M.Inaji, J.Maeda, T.Okauchi, N.Ito, T.Suhara
  • Journal Title: Synapse (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] In vivo Brain Imaging of Progressive Striatal Degeneration in MPTP-treated monkeys using PET with multiple tracers
  • Author(s): Y.Nagai, S.Obayashi, K.Ando, M.Inaji, J.Maeda, T.Okauchi, N.Ito, T.Suhara
  • Journal Title: Synapse (In press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] In vivo Brain Imaging of Progressive Striatal Degeneration in MPTP-treated monkeys using PET with multiple tracers
  • Author(s): Y.Nagai, S.Obayashi, K.i Ando, M.Inaji, J.Maeda, T.Okauchi, N.Ito, T.Suhara
  • Journal Title: Synapse (In press)
• [Journal Article] Functional organization of monkey brain for abstract operation
  • Author(s): Obayashi S, Matsumoto R, Suhara T, Nagai Y, Maeda J, Okauchi T, Iriki, A.
  • Journal Title: Cortex In press
• [Journal Article] In vivo PET measurements with [^<11>C]PE2I to evaluate fetal mesencephalic transplantations to unilateral 6-OHDA-lesioned rats.
  • Author(s): Inaji M., Yoshizaki T., Okauchi T., Maeda J., Nagai Y., Okano H., Nariai T., OhnO K., Ando K., ^*Obayashi S., Suhara T.
  • Journal Title: Cell Transplantation in press