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.
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: 10mg/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 Ca(2+)/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 (30mg/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-beta-benzyloxyaspartate (10nmol/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.
Murai
Rina
R
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
Noda
Yukihiro
Y
Matsui
Kanae
K
Kamei
Hiroyuki
H
Mouri
Akihiro
A
Matsuba
Kazuhisa
K
Nitta
Astumi
A
Furukawa
Hiroshi
H
Nabeshima
Toshitaka
T
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D046353:Immobility Response, Tonic / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010622:Phencyclidine / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010622:Phencyclidine; D011188:Potassium