title: Implication of protein kinase C in the orexin-induced elevation of extracellular dopamine levels and its rewarding effect.
abstract: In the present study, we investigated the role of orexinergic systems in the activation of midbrain dopamine neurons. In an in vitro study, exposure to either orexin A or orexin B under superfusion conditions produced a transient increase in the intracellular Ca(2+) concentration through the phospholipase C (PLC)/protein kinase C (PKC) pathway via G(q11)alpha or Gbetagamma subunits in midbrain cultured neurons, which were shown to be tyrosine hydroxylase (TH)-positive cells, but not in purified midbrain astrocytes. Here we show that in vivo injection with a selective PKC inhibitor chelerythrine chloride or 2-{8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl}-3-1-methyl-1H-indol-3-ylmaleimide HCl (Ro-32-0432) into the ventral tegmental area (VTA) significantly suppressed the place preference and increased levels of dopamine in the nucleus accumbens (NAcc) induced by intra-VTA injection of orexins. These results strongly support the idea that activation of the orexin-containing neuron in the VTA leads to the direct activation of mesolimbic dopamine neurons through the activation of the PLC/PKC pathway via G(q11)alpha or Gbetagamma-subunit activation, which could be associated with the development of its rewarding effect.
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. narita@hoshi.ac.jp
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nagumo
authors.forename: Mayumi
authors.initials: M
authors.lastname: Miyatake
authors.forename: Daigo
authors.initials: D
authors.lastname: Ikegami
authors.forename: Kana
authors.initials: K
authors.lastname: Kurahashi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis / Q000379:methods; D009479:Neuropeptides / Q000494:pharmacology*; D000068797:Orexins; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D000906:Antibodies; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D014446:Tyrosine 3-Monooxygenase; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D002118:Calcium; D004298:Dopamine