WAY208466 inhibits glutamate release at hippocampal nerve terminals

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• 作者：Hue Yu Wang^a ; ^b ; Cheng Wei Lu^c ; ^d ; Tzu Yu Lin^c ; ^d ; Jinn Rung Kuo^e ; ^f ; Su Jane Wang^g ; ^{med0003@mail.fju.edu.tw" class="auth_mail" title="E-mail the corresponding author}
• 关键词：5-HT6 receptor ; WAY208466 ; Antidepressant ; Glutamate ; Synaptosomes ; Hippocampus
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：781
• 期：Complete
• 页码：117-127
• 全文大小：971 K

文摘

Evidence suggests that the glutamatergic system plays a crucial role in the pathophysiology and treatment of depression. This study investigates the effect of WAY208466, a 5-HT₆ receptor agonist exhibiting an antidepressant effect, on glutamate release from rat hippocampal nerve terminals (synaptosomes). WAY208466 inhibited the Ca²⁺-dependent release of glutamate that was evoked by exposing the synaptosomes to the potassium channel blocker 4-aminopyridine, and the selective 5-HT₆ receptor antagonist SB258585 blocked this phenomenon. The WAY208466-mediated inhibition of glutamate release was associated with a reduction of 4-aminopyridine-induced increase in the cytosolic free Ca²⁺ concentration ([Ca²⁺]_C) mediated via Ca_v2.2 (N-type) and Ca_v2.1 (P/Q-type) channels. WAY208466 did not alter the resting synaptosomal membrane potential or 4-aminopyridine-mediated depolarization; thus, the inhibition of the Ca²⁺ influx could not be attributed to the decrease in synaptosomal excitability caused by 5-HT₆ receptor activation. Furthermore, the effect of WAY208466 on 4-aminopyridine-evoked glutamate release was prevented by a Gi/Go-protein inhibitor pertussis toxin, adenylate cyclase inhibitor SQ22536, and a protein kinase A inhibitor H89. These results suggest that WAY208466 acts at the 5-HT₆ receptors present in the hippocampal nerve terminals to suppress the Gi/Go-protein-coupled adenylate cyclase/protein kinase A cascade, which subsequently reduces the Ca²⁺ influx via N- and P/Q-type Ca²⁺ channels to inhibit the evoked glutamate release. This finding implicated a potential therapeutic role of 5-HT₆ receptor agonist in the treatment of depression and other neurological diseases associated with glutamate excitotoxicity.