Neurosci Lett. 2014 Feb 10;564C:72-77.

Chronic phencyclidine treatment induces long-lasting glutamatergic activation of VTA dopamine neurons

Kazuhide UramuraadYuko Maejimaa1Kenju Shimomuraa, 1Putra Santosoa1Shin-ichiro Katsudab,Daisuke KobayashibEiichi JodocMisato KodairaaZesemdorj Otgon-UulaYifei YangaKazuya Sakumaa,Morikuni TakigawadAkihiro HazamabToshihiko Yadaa

1) These four authors contributed equally.

a Department of Physiology,Division of Integrative Physiology,Jichi Medical University,School of Medicine,Shimotsuke,Tochigi,Japan
b Department of Cellular and Integrative Physiology,Fukushima MedicalUniversity,School of Medicine,Fukushima,Japan
c Department of Neurophysiology,Fukushima Medical University,School of Medicine,Fukushima,Japan
d Department of Neuropsychiatry,Faculty of Medicine,Kagoshima University,Kagoshima,Japan



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 Ca2+ concentration ([Ca2+]i) followed by immunocytochemical identification of dopamine neurons. Administration of glutamate increased [Ca2+]i in dopamine neurons from control rats, and the [Ca2+]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 [Ca2+]i increase in the presence of PCP. Furthermore, this glutamate-induced [Ca2+]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 [Ca2+]i increase in the presence of PCP was not observed or significantly attenuated under Ca2+ free condition and by N-type Ca2+ 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.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS: Dopamine, Mesolimbic pathway, Phencyclidine, Schizophrenia

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