Hyperactivity of Endoplasmic Reticulum Associated Exocytosis Mechanism Contributes to Acute Phencyclidine Intoxication

[摘要] References(48)Cited-By(13)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.

[学科分类] 药学

[关键词] phencyclidine;exocytosis;endoplasmic-reticulum;schizophrenia;microdialysis