• Biomolecules & Therapeutics
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• v.30 no.2
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• pp.191-202
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• 2022

Tetrazoles were designed and synthesized as potential inhibitors of triple monoamine neurotransmitters (dopamine, norepinephrine, serotonin) reuptake based on the functional and docking simulation of compound 6 which were performed in a previous study. The compound structure consisted of a tetrazole-linker (n)-piperidine/piperazine-spacer (m)-phenyl ring, with tetrazole attached to two phenyl rings (R1 and R2). Altering the carbon number in the linker (n) from 3 to 4 and in the spacer (m) from 0 to 1 increased the potency of serotonin reuptake inhibition. Depending on the nature of piperidine/piperazine, the substituents at R1 and R2 exerted various effects in determining their inhibitory effects on monoamine reuptake. Docking study showed that the selectivity of tetrazole for different transporters was determined based on multiple interactions with various residues on transporters, including hydrophobic residues on transmembrane domains 1, 3, 6, and 8. Co-expression of dopamine transporter, which lowers dopamine concentration in the biophase by uptaking dopamine into the cells, inhibited the dopamine-induced endoctytosis of dopamine D₂ receptor. When tested for compound 40 and 56, compound 40 which has more potent inhibitory activity on dopamine reuptake more strongly disinhibited the inhibitory activity of dopamine transporter on the endocytosis of dopamine D₂ receptor. Overall, we identified candidate inhibitors of triple monoamine neurotransmitter reuptake and provided a theoretical background for identifying such neurotransmitter modifiers for developing novel therapeutic agents of various neuropsychiatric disorders.

• The Korean Journal of Pharmacology
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• v.24 no.1
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• pp.17-29
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• 1988

The author examined the effects of lidocaine on the veratrine-or potassium-induced release of neurotransmitters to determine the possible role of amino acid neurotransmitters in lidocaine-induced convulsion. The examined transmitters were gamma-aminobutyric acid (GABA), aspartic acid, glutamic acid and norepinephrine which are released from the synaptosomes. Furthermore, the effects of lidocaine on the binding to receptors and synaptosomal uptake of the two transmitters, GABA and glutamic acid, were determined in crude synaptic membranes and synaptosomes. In addition, the effects of propranolol, norepinephrine and serotonin on the release of amino acid neurotransmitters were also examined. The veratrine-induced release of GABA was most severely inhibited by lidocaine and propranolol, while norepinephrine and serotonin reduced the release of aspartic acid and glutamic acid more than the GABA release. Generally the potassium-induced release was much more resistant to the lidocaine action than the veratrine-induced release. Among the neurotransmitters examined, the aspartic acid release was most prone to the lidocaine action, while the GABA release was most resistant. Concentrations of lidocaine below 1 mM did not significantly change the GABA and glutamic acid receptor binding and uptake. These results indicate that the blocking of sodium channels by lidocaine can result in the selective depression of the GABA release. This may result in unlimited excitation of the central nervous system.

• Korean Journal of Biological Psychiatry
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• v.12 no.1
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• pp.3-12
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• 2005

Most suicides(about 90%) occur in the context of psychiatric disorders. Prediction of suicide risk in patients with mental illness is very important in preventing suicide attempts. However, current approaches to predict suicidality are based on clinical history and have low specificity and biological markers are not yet included. Many studies have explored the association between different biological parameters and suicidality. Studies of cerebro-spinal fluid(CSF) demonstrated that 5-HIAA and HVA levels were lower in patients with a history of suicide. Platelet serotonin transporter and the 5-HT2 serotonin receptor have also been studied in relation to violence and suicide. Depressive patients with greater suicidal tendency had significantly lower cholesterol concentrations but some researchers failed to find the correlation. DST non-supression is reported to predict suicidality in major depression. Several studies demonstrated a relationship between intron 7 polymorphism of tryptophan hydroxylase and suicidal behavior. Since suicide is not occurred in a single disease, the systematic and comprehensive study in large samples with various diagnoses is necessary to find the biological and genetic predictors of suicidal behavior.

• The Korean Journal of Physiology and Pharmacology
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• v.7 no.5
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• pp.279-282
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• 2003

To investigate the effect of fluoxetine, one of selective serotonin reuptake inhibitors (SSRIs), on the immune system, human peripheral blood mononuclear cells (PBMC) were treated with fluoxetine $(10^{-7}\;M)$ for 24 h, and immune-related genes were analyzed by cDNA microarray. Expression of the immunerelated genes such as CD107b (LAMP-2), CD47 receptor (thrombospondin receptor), CD5 antigen-like (scavenger receptor cysteine rich family), copine III (CPNE3), interleukin (IL)-18 (interferon-gammainducing factor), integrin alpha 4 (CD49d), integrin alpha L subunit (CD11a), IL-3 receptor alpha subunit, L apoferritin, and small inducible cytokine subfamily A (Cys-Cys) member 13 (SCYA13) was induced by fluoxetine. This result suggests that fluoxetine may affect the immune system, and provides fundamental data for the involvement of SSRIs on immunoregulation.

• Biomolecules & Therapeutics
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• v.28 no.3
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• pp.282-291
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• 2020

Inhaled solvents such as toluene are of particular concern due to their abuse potential that is easily exposed to the environment. The inhalation of toluene causes various behavioral problems, but, the effect of short-term exposure of toluene on changes in emotional behaviors over time after exposure and the accompanying pathological characteristics have not been fully identified. Here, we evaluated the behavioral and neurochemical changes observed over time in mice that inhaled toluene. The mice were exposed to toluene for 30 min at a concentration of either 500 or 2,000 ppm. Toluene did not cause social or motor dysfunction in mice. However, increased anxiety-like behavior was detected in the short-term after exposure, and depression-like behavior appeared as delayed effects. The amount of striatal dopamine metabolites was significantly decreased by toluene, which continued to be seen for up to almost two weeks after inhalation. Additionally, an upregulation of serotonin 1A (5-HT_1A) receptor in the hippocampus and the substantia nigra, as well as reduced immunoreactivity of neurogenesis markers in the dentate gyrus, was observed in the mice after two weeks. These results suggest that toluene inhalation, even single exposure, mimics early anxiety-and delayed depression-like emotional disturbances, underpinned by pathological changes in the brain.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.2
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• pp.149-153
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• 2014

Nausea and emesis are a major side effect and obstacle for chemotherapy in cancer patients. Employ of antiemetic drugs help to suppress chemotherapy-induced emesis in some patients but not all patients. Ginger, an herbal medicine, has been traditionally used to treat various kinds of diseases including gastrointestinal symptoms. Ginger is effective in alleviating nausea and emesis, particularly, for cytotoxic chemotherapy drug-induced emesis. Ginger-mediated antiemetic effect has been attributed to its pungent constituents-mediated inhibition of serotonin (5-HT) receptor activity but its cellular mechanism of action is still unclear. Emetogenic chemotherapy drugs increase 5-HT concentration and activate visceral vagal afferent nerve activity. Thus, 5-HT mediated vagal afferent activation is essential to provoke emesis during chemotherapy. In this experiment, water extract of ginger and its three major pungent constituent's effect on 5-HT-evoked responses were tested on acutely dispersed visceral afferent neurons with patch-clamp methods. The ginger extract has similar effects to antiemetic drug ondansetron by blocking 5-HT-evoked responses. Pungent constituents of the ginger, [6]-shogaol, [6]-gingerol, and zingerone inhibited 5-HT responses in a dose dependent manner. The order of inhibitory potency for these compounds were [6]-shogaol>[6]-gingerol>zingerone. Unlike well-known competitive 5-HT3 receptor antagonist ondansetron, all tested ginger constituents acted as non-competitive antagonist. Our results imply that ginger and its pungent constituents exert antiemetic effects by blocking 5-HT-induced emetic signal transmission in vagal afferent neurons.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.4
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• pp.407-414
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• 2016

This study was performed to investigate whether the spinal cholinergic and serotonergic analgesic systems mediate the relieving effect of electroacupuncture (EA) on oxaliplatin-induced neuropathic cold allodynia in rats. The cold allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) was evaluated by immersing the rat's tail into cold water ($4^{\circ}C$) and measuring the withdrawal latency. EA stimulation (2 Hz, 0.3-ms pulse duration, 0.2~0.3 mA) at the acupoint ST36, GV3, or LI11 all showed a significant anti-allodynic effect, which was stronger at ST36. The analgesic effect of EA at ST36 was blocked by intraperitoneal injection of muscarinic acetylcholine receptor antagonist (atropine, 1 mg/kg), but not by nicotinic (mecamylamine, 2 mg/kg) receptor antagonist. Furthermore, intrathecal administration of $M_2$ (methoctramine, $10{\mu}g$) and $M_3$ (4-DAMP, $10{\mu}g$) receptor antagonist, but not $M_1$ (pirenzepine, $10{\mu}g$) receptor antagonist, blocked the effect. Also, spinal administration of $5-HT_3$ (MDL-72222, $12{\mu}g$) receptor antagonist, but not $5-HT_{1A}$ (NAN-190, $15{\mu}g$) or $5-HT_{2A}$ (ketanserin, $30{\mu}g$) receptor antagonist, prevented the anti-allodynic effect of EA. These results suggest that EA may have a significant analgesic action against oxaliplatin-induced neuropathic pain, which is mediated by spinal cholinergic ($M_2$, $M_3$) and serotonergic ($5-HT_3$) receptors.

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.1
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• pp.65-70
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• 2012

Synaptic long-term potentiation (LTP) and long-term depression (LTD) have been studied as mechanisms of ocular dominance plasticity in the rat visual cortex. Serotonin (5-hydroxytryptamine, 5-HT) inhibits the induction of LTP and LTD during the critical period of the rat visual cortex (postnatal 3~5 weeks). However, in adult rats, the increase in 5-HT level in the brain by the administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine reinstates ocular dominance plasticity and LTP in the visual cortex. Here, we investigated the effect of 5-HT on the induction of LTP in the visual cortex obtained from 3- to 10-week-old rats. Field potentials in layer 2/3, evoked by the stimulation of underlying layer 4, was potentiated by theta-burst stimulation (TBS) in 3- and 5-weekold rats, then declined to the baseline level with aging to 10 weeks. Whereas 5-HT inhibited the induction of LTP in 5-week-old rats, it reinstated the induction of N-methyl-D-aspartate receptor (NMDA)-dependent LTP in 8- and 10-week-old rats. Moreover, the selective SSRI citalopram reinstated LTP. The potentiating effect of 5-HT at 8 weeks of age was mediated by the activation of 5-$HT_2$ receptors, but not by the activation of either 5-$HT_{1A}$ or 5-$HT_3$ receptors. These results suggested that the effect of 5-HT on the induction of LTP switches from inhibitory in young rats to facilitatory in adult rats.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.267.3-268
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• 2002

Aggregation of the high affinity 1gE receptor on mast cells results in many biochemical. events leading to the release of histamine. serotonin. prostaglandins arachidonic acid metabolites, and cytokines. Previously we have shown that M2 pyruvate kinase interacts with the gamma chain of 1gE receptor on the ITAM (immunoreceptor tyrosine-based activation motif) region. (omitted)

• Biomolecules & Therapeutics
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• v.4 no.1
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• pp.36-45
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• 1996

The antihistaminic action of eighteen herbal medicines was investigated by the radioligand binding and functional assays. The hexane fractions of Trichosanthis radix, Mori cortex radicis and Evodiae fructus dosedependently inhibited [$^3$H] mepyramine binding to H$_1$, receptor in guinea-pig brain homogenates and histamine-induced contraction of isolated guinea-pig ileum. Antihistaminic action of the hexane and ethyl acetate fractions of Mori cortex radicis and the hexane fraction of Evodiae fructus was more potent than their antimuscarinic action evaluated from the inhibition of [$^3$H]QNB binding and carbachol response. The ethyl acetate and chloroform fractions from Scutellariae radix also inhibited histamine-induced contraction, but antihistaminic potencies of these fractions were almost identical with their antimuscarinic potencies. The hexane fractions of Mori cortex radicis and Evodiae fructus inhibited selectively the increase of histamine-induced cutaneous vascular Permeability in the rat dorsal skins. However, the ethyl acetate fraction from Scutellariae radix inhibited eqipotently the effects of histamine and serotonin on the vascular permeability. These results demonstrate that the hexane and ethyl acetate fractions of Mori cortex radicis and the hexane fraction of Evodiae fructus have the selective histamine H$_1$receptor blocking activity.