Inhibition of glutamate release by fluspirilene in cerebrocortical nerve terminals (synaptosomes).
Fluspirilene, a neuroleptic drug which is used clinically to treat schizophrenic patients, is a dopamine D2 receptor antagonist. Besides its well-known actions on the dopamine receptors, fluspirilene also displays calcium channel-blocking activity. The aim of this study was to investigate the effect of fluspirilene on the 4-aminopyridine (4AP)-evoked glutamate release in the cerebrocortical nerve terminals (synaptosomes). Fluspirilene reduced 4AP-evoked glutamate release in a concentration-dependent manner. This inhibitory effect was associated with a decrease in the depolarization-evoked increase in the cytoplasmic free Ca2+ concentration ([Ca2+]C), which could be completely abolished by the Ca2+ channel blocker omega-CgTX GVIA. Furthermore, fluspirilene did not produce any effect on ionomycin-evoked glutamate release. These results suggest that fluspirilene inhibits glutamate release primarily by reducing presynaptic Ca2+ influx via N-type Ca2+ channels in rat cerebrocortical nerve terminals. This finding implies that presynaptic Ca2+ channel blockade concomitant with inhibition of glutamate release and possibly other neurotransmitters release may contribute to the antischizophrenic action of fluspirilene.
Wang
Su-Jane
SJ
School of Medicine, Fu Jen Catholic University, Hsin-Chuang, Taipei Hsien, Taiwan 24205. med0003@mails.fju.edu.tw
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004347:Drug Interactions; D005484:Fluspirilene / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes
D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D018492:Dopamine Antagonists; D007476:Ionophores; D026902:Potassium Channel Blockers; D018698:Glutamic Acid; D015761:4-Aminopyridine; D005484:Fluspirilene; D002118:Calcium