Fluoxetine depresses glutamate exocytosis in the rat cerebrocortical nerve terminals (synaptosomes) via inhibition of P/Q-type Ca2+ channels.
Fluoxetine, an antidepressant that is used clinically in the treatment of mood disorders, is a selective serotonin reuptake inhibitor. In the present study we investigated the effects of fluoxetine on 4-aminopyridine (4AP)-evoked glutamate release in cerebrocortical nerve terminals (synaptosomes). Fluoxetine suppressed the release of glutamate evoked by 4AP in a concentration-dependent manner. This effect was associated with a reduction in the depolarization-evoked increase in cytosolic free calcium levels in the absence of significant effect on the synaptosomal membrane potential. In addition, both ionomycin- and sucrose-evoked glutamate releases were not affected by fluoxetine, indicating that fluoxetine-mediated inhibition of glutamate release is not a direct effect on the exocytotic machinery. Furthermore, the inhibitory action of fluoxetine was completely abolished in synaptosomes pretreated with P/Q type Ca(2+) channel blocker omega-agatoxin IVA (omega-AgTX IVA) or protein kinase C (PKC) stimulator 4beta-phorbol 12, 13-dibutyrate (PDBu). These results suggest that, in cerebrocortical nerve terminals, fluoxetine inhibits glutamate release through the suppression of P/Q type Ca(2+) channel activity. The presynaptic action of fluoxetine is mediated by a PKC-sensitive signaling pathway. Synapse 48:170-177, 2003.
Wang
Su-Jane
SJ
School of Medicine, Fu Jen Catholic University, Hsin-Chuang, Taipei Hsien, Taiwan 24205. med0003@mails.fju.edu.tw
Su
Chin-Feng
CF
Kuo
Yu-Heng
YH
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D020865:Calcium Channels, P-Type / Q000187:drug effects*; D020907:Calcium Channels, Q-Type / Q000187:drug effects*; D002540:Cerebral Cortex / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects*; D005473:Fluoxetine / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013574:Synaptosomes / Q000378:metabolism*
D015761:4-Aminopyridine; D018687:Antidepressive Agents, Second-Generation; D002118:Calcium; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D005473:Fluoxetine; D018698:Glutamic Acid; D018377:Neurotransmitter Agents; D026902:Potassium Channel Blockers; D011493:Protein Kinase C; D017367:Selective Serotonin Reuptake Inhibitors