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

Abstract

Abstract. Phencyclidine (PCP) produces schizophrenia-like psychosis and acute PCPintoxications; 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 prefrontalcortex (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 PCPassociated 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.

Effects of quetiapine on monoamine, GABA, and glutamate release in rat prefrontal cortex

“…Perfusion of MK-801 also enhanced the stimulatory effect of QTP on norepinephrine, dopamine, and glutamate releases, whereas under the same condition, serotonin and GABA releases were unaffected. Several previous studies also demonstrated that local perfusion with NMDA receptor antagonist increased the extracellular monoamine level in mPFC (Lorrain et al 2003;Yonezawa et al 1998;Zhu et al 2004). In contrast, a previous study reported that systemic administration of MK-801 increased frontal extracellular serotonin level, whereas local perfusion of 300 μM MK-801 with 1 μM citalopram did not affect the extracellular serotonin level in mPFC (Lopez-Gil et al 2007).…”

“…The major dopaminergic, noradrenergic, and serotoninergic afferents project to deep layers of the mPFC from the VTA, LC, and DRN, respectively, but the major glutamatergic afferents project from other cortical regions to the superficial layers of the mPFC (Cotman and Monaghan 1986;Jay et al 1992;Kuroda et al 1998;Lambe et al 2000;Van Eden et al 1987;Waterhouse et al 1983). Contacts between glutamatergic and monoaminergic neurons in the mPFC are mainly indirect and mediated by GABAergic interneurons, which are regulated by stimulatory NMDA/glutamate receptors (Yonezawa et al 1998;Zhu et al 2004). The present study demonstrated the stimulatory effects of QTP administered systemically on neuronal activities in the VTA, LC, and MTN, but not the DRN.…”

“…Interaction between local perfusion of muscimol and systemic administration of QTP on neurotransmitter release in mPFC Two-way ANOVA indicated significant effects of perfusion of 50 μM muscimol Yonezawa et al 1998;Zhu et al 2004) (Fig. 6), but not on the levels of serotonin or GABA (Fig.…”

Intracellular CICR -associated pharmacological mechanism of action of antiepileptic drugs

“…These observations suggest that RyR tends to be nonfunctional during the resting stage while the potential of RyRsensitive CICR in neurotransmitter release could conceivably be promoted during the neuronal hyperexcitable stage [28,29,33]. The elevation of intracellular Ca 2+ concentration in the active zone induced by neuronal hyperexcitability and/or overload response of CICR may reduce neurotransmitter exocytosis [28,29,33,34,[36][37][38]. Therefore, activated RyR enhances the releases of glutamate and GABA, whereas hyperactivation of ryanodine sensitive CICR could lead to an imbalance between GABAergic and glutamatergic transmissions via predominantly breakdown of GABAergic transmission, induced by overload response of Ca 2+ mobilization [28,29,38].…”

“…Especially, ZNS has been well established as a major AED against both partial and generalized seizures in Japan [5]. The major mechanisms of antiepileptic actions of CBZ and ZNS are considered to be their inhibitory effects on voltage-gated Na + channel (VGSC) [13,14] -release system (CICR) [28][29][30][31][32][33][34][35][36][37][38]. The functional importance of CICRs in the pathogenesis of epileptic seizure and neuronal damage associated with epilepsy has been demonstrated by several studies [39][40][41][42].…”