• The Korean Journal of Physiology and Pharmacology
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• v.22 no.5
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• pp.585-595
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• 2018

Amitriptyline, a tricyclic antidepressant, is commonly used to treat depression and neuropathic pain, but its mechanism is still unclear. We tested the effect of amitriptyline on 5-hydroxytryptamine 3 ($5-HT_3$) receptor currents and studied its blocking mechanism because the clinical applications of amitriptyline overlapped with $5-HT_3$ receptor therapeutic potentials. Using a whole-cell voltage clamp method, we recorded the currents of the $5-HT_3$ receptor when 5-HT was applied alone or co-applied with amitriptyline in cultured NCB-20 neuroblastoma cells known to express $5-HT_3$ receptors. To elucidate the mechanism of amitriptyline, we simulated the $5-HT_3$ receptor currents using Berkeley $Madonna^{(R)}$ software and calculated the rate constants of the agonist binding and receptor transition steps. The $5-HT_3$ receptor currents were inhibited by amitriptyline in a concentration-dependent, voltage-independent manner, and a competitive mode. Amitriptyline accelerated the desensitization of the $5-HT_3$ receptor. When amitriptyline was applied before 5-HT treatment, the currents rose slowly until the end of 5-HT treatment. When amitriptyline was co-applied with 5-HT, currents rose and decayed rapidly. Peak current amplitudes were decreased in both applications. All macroscopic currents recorded in whole cell voltage clamping experiments were reproduced by simulation and the changes of rate constants by amitriptyline were correlated with macroscopic current recording data. These results suggest that amitriptyline blocks the $5-HT_3$ receptor by close and open state blocking mechanisms, in a competitive manner. We could expand an understanding of pharmacological mechanisms of amitriptyline related to the modulation of a $5-HT_3$ receptor, a potential target of neurologic and psychiatric diseases through this study.

• The Korean Journal of Physiology and Pharmacology
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• v.23 no.6
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• pp.509-517
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• 2019

Escitalopram is one of selective serotonin reuptake inhibitor antidepressants. As an S-enantiomer of citalopram, it shows better therapeutic outcome in depression and anxiety disorder treatment because it has higher selectivity for serotonin reuptake transporter than citalopram. The objective of this study was to determine the direct inhibitory effect of escitalopram on 5-hydroxytryptamine type 3 ($5-HT_3$) receptor currents and study its blocking mechanism to explore additional pharmacological effects of escitalopram through $5-HT_3$ receptors. Using a wholecell voltage clamp method, we recorded currents of $5-HT_3$ receptors when 5-HT was applied alone or co-applied with escitalopram in cultured NCB-20 neuroblastoma cells known to express $5-HT_3$ receptors. 5-HT induced currents were inhibited by escitalopram in a concentration-dependent manner. $EC_{50}$ of 5-HT on $5-HT_3$ receptor currents was increased by escitalopram while the maximal peak amplitude was reduced by escitalopram. The inhibitory effect of escitalopram was voltage independent. Escitalopram worked more effectively when it was co-applied with 5-HT than pre-application of escitalopram. Moreover, escitalopram showed fast association and dissociation to the open state of $5-HT_3$ receptor channel with accelerating receptor desensitization. Although escitalopram accelerated $5-HT_3$ receptor desensitization, it did not change the time course of desensitization recovery. These results suggest that escitalopram can inhibit $5-HT_3$ receptor currents in a non-competitive manner with the mechanism of open channel blocking.

• Radiation Oncology Journal
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• v.17 no.2
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• pp.141-145
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• 1999

Purpose : Granisetron is a potent, the most selective 5-HT3 receptor antagonist and is reported to b effective in treatment of radiation-induced emesis. The antiemetic efficacy and safety of oral granisteron was evaluated in patients with receiving highly emetogenic treatment by conventional fractionated irradiation. Materials and Methods : Patients with various cancers who were being treated with irradiation were accrued into the present study. The intensity of nausea was evaluated on first 24 hours and on day-7 by patients according to the degree of interference with normal daily life as followings; a) none; b) present but no interference with normal daily life (mild): c) interference with normal daily life (moderate): and d) bedridden because of nausea (severe). Non or mild state was considered to indicate successful treatment. The efficacy of antiemetic treatment was graded as follows; a) complete response; no vomiting, no worse than mild nausea and receive no rescue antiemetic therapy over the 24h period, b) major response; either one episode of vomiting or moderate/severe nausea or had received rescue medication over 24h period, or any combination of these, c) minor response; two to four episodes of vomiting over the 24h period, regardless of nausea and rescue medication, d) failure; more than four medication. The score of the most symptom was recorded and the total score over 24 hours was summarized. The complete or major response was considered to indicate successful treatment. Results : A total of 10 patients were enrolled into this study, and all were assessable for efficacy analysis. Total nausea control was achieved in 90$\%$ (9/10:none=60$\%$ plus mild=30$\%$) of total patients after 7 days. The control of vomiting by granisteron was noted in seven patients (70$\%$) of complete response and three (30$\%$) of major response with a hundred-percent successful treatment over 7 days. The minor response or treatment failure were not observed. No significant adverse events or toxicities from granisetron were recorded in patient receiving granisetron. Conclusion : We concluded that granisetron is a highly effective antiemetic agent in controlling radiotherapy-induced nausea or vomiting with a minimal toxicity profile.