title: WAY208466 inhibits glutamate release at hippocampal nerve terminals.
abstract: 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 Ca(2+)-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 Ca(2+) concentration ([Ca(2+)]C) mediated via Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels. WAY208466 did not alter the resting synaptosomal membrane potential or 4-aminopyridine-mediated depolarization; thus, the inhibition of the Ca(2+) 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 Ca(2+) influx via N- and P/Q-type Ca(2+) 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.
authors.affiliation: Department of Pharmacy, Chi-Mei Medical Center, Tainan, Taiwan; College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hue Yu
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan; Department of Mechanical Engineering, Yuan Ze University, Taoyuan 320, Taiwan.
authors.forename: Cheng Wei
authors.initials: CW
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan; Department of Mechanical Engineering, Yuan Ze University, Taoyuan 320, Taiwan.
authors.forename: Tzu Yu
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Department of Neurology, Chi Mei Medical Center, Tainan, Taiwan; Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.
authors.forename: Jinn Rung
authors.initials: JR
authors.lastname: Kuo
authors.affiliation: School of Medicine, Fu Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei 24205, Taiwan. Electronic address: med0003@mail.fju.edu.tw.
authors.forename: Su Jane
authors.initials: SJ
authors.lastname: Wang
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D008297:Male; D008744:Methylamines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D015761:4-Aminopyridine; D000262:Adenylyl Cyclases; D002118:Calcium; D020864:Calcium Channels, N-Type; D017868:Cyclic AMP-Dependent Protein Kinases; D018698:Glutamic Acid; D008744:Methylamines; D011725:Pyridines; D012702:Serotonin Antagonists; C503279:Cacna1b protein, rat; C558330:N-(2-(3-(3-fluorophenylsulfonyl)-1H-pyrrolo(2,3-b)pyridin-1-yl)ethyl)-N,N-dimethylamine
keywords: 5-HT(6) receptor; Antidepressant; Glutamate; Hippocampus; Synaptosomes; WAY208466