Hyperactivity of endoplasmic reticulum associated exocytosis mechanism contributes to acute phencyclidine intoxication.
Phencyclidine (PCP) produces schizophrenia-like psychosis and acute PCP-intoxications; however, whether glutamate/NMDA-receptor blockade by PCP modulates or not these mechanisms has remained to be clarified. To clarify this mechanism, we determined interaction among voltage-gated Na(+)-channel inhibitor, tetrodotoxin (TTX), Golgi-disturbing-agent, brefeldin-A (BFA), and PCP on releases of glutamate, GABA, and monoamine in prefrontal-cortex (pFC), using microdialysis. PCP increased basal monoamine release, whereas it decreased basal GABA release, without affecting glutamate release. PCP increased K(+)-evoked monoamine release, whereas it decreased K(+)-evoked glutamate and GABA releases. TTX reduced basal monoamine and GABA releases without affecting glutamate release, whereas BFA did not affect them. Interestingly, BFA and TTX inhibited PCP-associated basal monoamine release and abolished PCP-induced reduction of basal GABA release without affecting glutamate release. BFA and TTX reduced K(+)-evoked releases of all neurotransmitters. BFA inhibited PCP-associated K(+)-evoked monoamine release, but TTX did not affect them. PCP-induced reduction of K(+)-evoked GABA and glutamate releases was abolished by TTX and BFA. These results indicate that PCP reduces GABAergic transmission via NMDA-receptor blockade and activates intracellular endoplasmic-reticulum-associated signal-transduction, resulting in enhancement of monoaminergic transmission in pFC. Thus, these PCP properties support the hypothesis that mechanisms of the neurological symptoms of acute PCP-intoxication, convulsion, and rhabdomyolysis may be involved in both reduction of GABAergic-transmission and activation of endoplasmic-reticulum-associated signal-transduction induced by PCP.
Zhu
Gang
G
Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan.
Okada
Motohiro
M
Uchiyama
Daishi
D
Ohkubo
Tadashi
T
Yoshida
Shukuko
S
Kaneko
Sunao
S
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004058:Diffusion; D004347:Drug Interactions; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005089:Exocytosis / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D018377:Neurotransmitter Agents / Q000378:metabolism; D010622:Phencyclidine / Q000633:toxicity*; D011188:Potassium / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013238:Stereotaxic Techniques; D013779:Tetrodotoxin / Q000494:pharmacology
D000779:Anesthetics, Local; D018691:Excitatory Amino Acid Antagonists; D018377:Neurotransmitter Agents; D011500:Protein Synthesis Inhibitors; D020126:Brefeldin A; D013779:Tetrodotoxin; D010622:Phencyclidine; D011188:Potassium