Hypofunctional glutamatergic neurotransmission in the prefrontal cortex is involved in the emotional deficit induced by repeated treatment with phencyclidine in mice: Implications for abnormalities of glutamate release and NMDA-CaMKII signaling

Rina Murai, Yukihiro Noda, Kanae Matsui, Hiroyuki Kamei, Akihiro Mouri, Kazuhisa Matsuba, Astumi Nitta, Hiroshi Furukawa, Toshitaka Nabeshima

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Abstract

In the present study, we investigated the involvement of prefrontal glutamatergic neurotransmission in the enhancement of immobility (emotional deficit) in a forced swimming test in mice treated with phencyclidine (PCP: 10 mg/kg/day for 14 days) repeatedly, which is regarded as an animal model for negative symptoms. A decrease in spontaneous extracellular glutamate release and increase in levels of the glutamate transporter GLAST, were observed in the prefrontal cortex (PFC) of PCP-treated mice, compared to saline-treated mice. NMDA receptor subunit 1 (NR1) and Ca2+/calmoduline kinase II (CaMKII) were markedly activated in the PFC of saline-treated mice, but not PCP-treated mice, immediately after the forced swimming test. The facilitation of the function of NMDA receptors by d-cycloserine (30 mg/kg i.p.), an NMDA receptor glycine-site partial agonist, reversed the enhancement of immobility in the forced swimming test and impairment of CaMKII activation in the PCP-treated mice. Microinjection of dl-threo-β-benzyloxyaspartate (10 nmol/site/bilaterally), a potent blocker of glutamate transporters, into the PFC of PCP-treated mice also had an attenuating effect. In addition, activation of glial cells and a decrease of neuronal cell size were observed in the PFC of PCP-treated mice. These results suggest that repeated PCP treatment disrupts pre- and post-synaptic glutamatergic neurotransmission and induces morphological changes in the PFC and that such changes cause the emotional deficits exhibited in PCP-treated mice.

Original languageEnglish
Pages (from-to)152-160
Number of pages9
JournalBehavioural Brain Research
Volume180
Issue number2
DOIs
Publication statusPublished - 18-06-2007
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Behavioral Neuroscience

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