title: Chronic phencyclidine treatment induces long-lasting glutamatergic activation of VTA dopamine neurons.
abstract: Use of phencyclidine (PCP) can mimic some aspects of schizophrenia. However, the underlying mechanism is unclear. Administration of PCP is known to activate mesolimbic dopamine pathway. In this study, we focused on ventral tegmental area (VTA) of mesolimbic dopamine pathway as target of PCP for inducing schizophrenia-like symptoms. Single VTA neuron was isolated and its neural activity was monitored by measuring cytosolic Ca(2+) concentration ([Ca(2+)]i) followed by immunocytochemical identification of dopamine neurons. Administration of glutamate increased [Ca(2+)]i in dopamine neurons from control rats, and the [Ca(2+)]i increase was inhibited in the presence of PCP. In contrast, in VTA dopamine neurons from rats chronically treated with PCP for 7 days, administration of glutamate was able to induce [Ca(2+)]i increase in the presence of PCP. Furthermore, this glutamate-induced [Ca(2+)]i increase in the presence of PCP continued even after washout of glutamate and this effect lasted as long as PCP was present. This long-lasting glutamate-induced [Ca(2+)]i increase in the presence of PCP was not observed or significantly attenuated under Ca(2+) free condition and by N-type Ca(2+) channel blocker ω-conotoxin. The results indicate that chronic treatment with PCP reverses the acute PCP effect on VTA dopamine neurons from inhibitory to stimulatory tone, and consequently induces long-lasting activation of dopamine neurons by glutamate.
authors: Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi, Japan; Department of Neuropsychiatry, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
authors: Kazuhide
authors: K
authors: Uramura
authors: Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi, Japan.
authors: Yuko
authors: Y
authors: Maejima
authors: Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi, Japan.
authors: Kenju
authors: K
authors: Shimomura
authors: Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi, Japan.
authors: Putra
authors: P
authors: Santoso
authors: Department of Cellular and Integrative Physiology, Fukushima Medical University, School of Medicine, Fukushima, Japan.
authors: Shin-Ichiro
authors: S
authors: Katsuda
authors: Department of Cellular and Integrative Physiology, Fukushima Medical University, School of Medicine, Fukushima, Japan.
authors: Daisuke
authors: D
authors: Kobayashi
authors: Department of Neurophysiology, Fukushima Medical University, School of Medicine, Fukushima, Japan.
authors: Eiichi
authors: E
authors: Jodo
authors: Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi, Japan.
authors: Misato
authors: M
authors: Kodaira
authors: Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi, Japan.
authors: Zesemdorj
authors: Z
authors: Otgon-Uul
authors: Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi, Japan.
authors: Yifei
authors: Y
authors: Yang
authors: Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi, Japan.
authors: Kazuya
authors: K
authors: Sakuma
authors: Department of Neuropsychiatry, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
authors: Morikuni
authors: M
authors: Takigawa
authors: Department of Cellular and Integrative Physiology, Fukushima Medical University, School of Medicine, Fukushima, Japan.
authors: Akihiro
authors: A
authors: Hazama
authors: Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi, Japan. Electronic address: tyada@jichi.ac.jp.
authors: Toshihiko
authors: T
authors: Yada
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology*; D008297:Male; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D010622:Phencyclidine
keywords: Dopamine; Mesolimbic pathway; Phencyclidine; Schizophrenia