• Journal of Animal Reproduction and Biotechnology
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• v.38 no.2
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• pp.77-83
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• 2023

Background: Serotonin receptors can be divided into seven different families with various subtypes. The serotonin 1A (5-HT1A) receptor is one of the most abundant subtypes in animal brains. The expression of 5-HT1A receptors in the brain has been reported in various animals but has not been studied in horses. The 5-HT1A receptor functions related to emotions and behaviors, thus it is important to understand the functional effects and distribution of 5-HT1A receptors in horses to better understand horse behavior and its associated mechanism. Methods: Brain samples from seven different regions, which were the frontal, central, and posterior cerebral cortices, cerebellar cortex and medulla, thalamus, and hypothalamus, were collected from six horses. Western blot analysis was performed to validate the cross-reactivity of rabbit anti-5-HT1A receptor antibody in horse samples. Immunofluorescence was performed to evaluate the localization of 5-HT1A receptors in the brains. Results: The protein bands of 5-HT1A receptor appeared at approximately 50 kDa in the frontal, central, and posterior cerebral cortices, cerebellar cortex, thalamus, and hypothalamus. In contrast, no band was observed in the cerebellar medulla. Immunofluorescence analysis showed that the cytoplasm of neurons in the cerebral cortices, thalamus, and hypothalamus were immunostained for 5-HT1A receptors. In the cerebellar cortex, 5-HT1A was localized in the cytoplasm of Purkinje cells. Conclusions: In conclusion, the study suggests that 5-HT and 5-HT1A receptor systems may play important roles in the central nervous system of horses, based on the widespread distribution of the receptors in the horse brain.

• The Korean Journal of Pharmacology
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• v.26 no.2
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• pp.153-160
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• 1990

5-Hydroxytryptamine (5-HT) was reported to elicit natriuresis and diuresis when given intracerebroventricularly (icv) and these effects were shown to be abolished by icv methysergide, $5-HT{_1}$ antagonist, thus suggesting that central tryptaminergic system may also participate in the regulation of renal function. We tried in this study to elucidate the role of $5-HT_2$ receptors in the central tryptaminergic regulation of renal function, observing the effects of icv ketanserin, a specific $5-HT_2$ antagonist. Ketanserin (KET) icv in doses of $120{\mu}g$ $(=0.3\;{\mu}moles)/kg$ produced significant natriuresis without affecting renal hemodynamics, indicating that it resulted from decreased tubular Na reabsorption. Systemic blood pressure decreased slightly but significantly. When given iv, no significant effect was observed. 5-HT, $200{\mu}g/kg$ icv, produced mild but significant natriuresis and diuresis. However, after KET, $40{\mu}\;g/kg$ icv, a dose which minimally affects renal function, the natriuresis and diuresis by 5-HT was greatly augmented, with the fractional excretion of filtered sodium reaching 9.3%. The renal effects of other biogenic amines administered icv, such as norepinephrine, dopamine and histamine, were not significantly affected by the KET pretreatment. These observations suggest that central tryptaminergic system influences renal function in dual ways, i.e., natriuretic and diuretic influence via $5-HT_1$ receptors, whereas $5-HT_2$ subtypes mediate the antinatriuretic and antidiuretic effects, and that the central tryptaminergic system plays a role in the regulation of rabbit renal function.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.3
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• pp.315-323
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• 1997

Central tryptaminergic system has been shown to play an important role in the regulation of renal function: $5-HT_1(5-hydroxytryptamine_1)$ receptors might seem to mediate the diuresis and natriuresis, whereas the $5-HT_2\;and\;5-HT_3$ receptors mediate the antidiuretic and antinatriuretic effects. This study attempted to delineate the role of central $5-HT_{1A}$ subtype in the regulation of rabbit renal function by observing the renal effects of intracerebrovent-ricularly(icv)-administered PAPP(p-aminorhenylethyl-m-trifluoromethytphenyl piperazine, LY165163), a selective agonist of $5-HT_{1A}$ receptors. PAPP in doses ranging from 40 to $350{\mu}g/kg$ icv induced significantly diuresis, natriuresis, and kaliuresis, along with increased renal perfusion and glomerular filtration. Systemic blood pressure was also increased. Free water reabsorption$(T^cH_2O)$, a measure of ADH(antidiuretic hormone) secretion, was increased also. Intravenous $350{\mu}g/kg$ of PAPP elicited antidiuresis and antinatriuresis together with decreased blood pressure, thus indicating that the effects of icv PAPP were brought about through the central mechanisms, not by direct peripheral effects of the drug on kidney. Ketanserin, a selective $5-HT_2$ antagonist, $40{\mu}g/kg$ icv, did not affect the renal effects of the icv PAPP. Methysergide, a non-selective $5-HT_1$ antagonist, also did not block the renal functional responses by the icv PAPP. NAN-190, a $5-HT_{1A}$ antagonist, also did not antagonized the renal action of the icv PAPP. However the increased free water reabsorption was abolished by both methysergide or ketanserin pretreatment. The increments of blood pressure by icv PAPP was blocked only by NAN-190 pretreatment. These observations suggest that the central $5-HT_{1A}$ receptor might be involved in the central regulation of rabbit renal function by exerting the diuretic and natriuretic influences.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1998.11a
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• pp.170-170
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• 1998

In order to discover new types of 5-hydroxytryptamine antagonists, we have devoted our attention to investigating naturally occurring compounds having anti-5HT activity in vitro. Recently, ${\gamma}$-mangostin [1,3,6,7-tetrahydroxy-2,8-bis(3-methyl-2-bytenyl)-9H-xanthen-9-one] from the fruit hull of Garcinia mangostana Linn has been shown to be a selective antagonist for 5-hydroxytryptamine$_{2A}$ receptors in smooth muscle and platelets. It is of interesting that y-mangostin which does not have a nitrogen atom, possesses marked 5-$HT_{2A}$ receptor blocking activity. The present study was undertaken to investigate the effects of ${\gamma}$-mangostin on central 5-HT receptors by using animal behavioural models. Intracerebronventricular injection of ${\gamma}$-mangostin (10-40n mol/mouse) inhibited 5-fluoro-${\alpha}$-methyltryptamin (5-FMT) (45 mg kg$^{-1}$, i.p.)-induced head-twitch response in mice in the presence or absence of citalopram (5-HT-uptake inhibitor). Neither the 5-FMT- nor the 8-hydroxy-2-( di-n-propylamino )tetralin (5-HT$_{1A}$-agonist)-induced 5-HT syndrome (head weaving and hindlimb abduction) was affected by ${\gamma}$-mangostin. The locomotor activity stimulated by 5-FMT through the activation of at-adrenoceptors did not alter in the presence of ${\gamma}$-mangostin. 5-HT-induced inositol phosphates accumulation in mouse brain slices was abolished by ketanserin. ${\gamma}$-Mangostin caused a concentration-dependent inhibition of the inositol phosphates accumulation and the binding of [$^3H$]-spiperone, a specific 5-$HT_{2A}$ receptor antagonist, to mouse brain membranes. Kinetic analysis of the [$^H3$]-spiperone binding revealed that ${\gamma}$-mangostin increased the $_{d}$ value without affecting the $B_{max}$ value, indicating the mode of the competitive nature of the inhibition by ${\gamma}$-mangostin. These results suggest that ${\gamma}$-mangostin inhibits 5-FMT-induced head-twitch response in mice by blocking 5-$HT_{2A}$ receptors not by blocking the release of 5-HT from the central neurone. ${\gamma}$-Mangostin is a promising 5-$HT_{2A}$ receptors antagonist in the central nervous system.m.

• Proceedings of the Korean Biophysical Society Conference
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• 2003.06a
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• pp.59-59
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• 2003

Serotonin (5-HT; 5-hydroxytryptamine) exerts multiple effects on central nervous system as well as behaviors such as mood and appetite. The signaling of serotonin is mediated by 7 families of serotonin receptors, designated 5-HT$_1$ to 5-HT$_{7}$. Six families of this receptor are G-protein coupled 7TM receptors, and the third intracellular loop of these receptors is proposed to interact with specific types of G-proteins. To investigate the specific interaction between the third intracellular loop of 5-HT$_{6}$ with G$\square$s, we have constructed a chimera protein that represent the third intracellular loop of 5-HT$_{6}$ within a leucine zipper motifs, In addition an alpha subunit of human G-protein that interact with 5-HT$_{6}$ was cloned into a bacterial expression vector. The two proteins were expressed in E. coli and purified in homogeneity. The interaction of the prepared proteins was examined by ELISA assay. The affinity between the two proteins and effect of insertion mutations were discussed.ussed.d.

• The Korean Journal of Pharmacology
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• v.28 no.2
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• pp.137-146
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• 1992

The central tryptaminergic system has been shown to play an important role in the regulation of renal function: $5-HT_1$ receptor mediate diuresis and natriuresis, whereas both $5-HT_2$ and $5-HT_3$ mediate antidiuresis and antinatriuresis. Recently, $5-HT_1$ receptors are further subdivided into many subtypes, and central $5-HT_{1A}$ subtype was shown to mediate diuretic and natriuretic effects. The present study was undertaken to delineate the role of $5-HT_{1B}$ subtype. Trifluoromethylphenylpiperazine (TFMPP), a selective $5-HT_{1B}$ agonist in doses ranging from 8 to $750\;{\mu}g/kg$ icv elicited diuresis, natriuresis and kaliuresis in dose-dependent fashion, with the fractional excretion of filtered Na reaching 5.44% with $250\;{\mu}g/kg$ icv. The natriuresis outlasted the transient increases in renal hemodynamics, suggesting humoral mediation in the decreased tubular Na reabsorption. Plasma concentration of atrial natriuretic peptide increased along with the natriuresis. Systemic blood pressure transiently increased. When given intravenously, no diuresis and natriuresis was elicited, indicating the central mechanism. The icv TFMPP effects were not significantly affected by icv methysergide, a nonselective $5-HT_1$ blocker. Both ketanserin and MDL 72222, selective $5-HT_2$ and $5-HT_3$ antagonists, resp., did not abolish the TFMPP effects. Nor did NAN-190, $5-HT_{1A}$ blocker, affect the TFMPP effects. These observations suggest that central $5-HT_{1B}$ receptors may play a role in the central regulation of renal function by exerting diuretic and natriuretic influences, mainly through natriuretic factors.

• Bulletin of the Korean Chemical Society
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• v.30 no.5
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• pp.1107-1112
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• 2009

The aim of this study is to develop and synthesize $5-HT_{1A}$ receptor imaging agents with WAY-100635 moiety and $^{99m}Tc(CO)_3$ core. WAY-100635 is commonly known as $5-HT_{1A}$ antagonist and its labeled compound ([$^{11}C$] WAY-100635) has been used as effective radioligand for imaging brain $5-HT_{1A}$ receptors with PET(Positron Emission Tomography). However, there are several restrictions in using a radioisotope of C-11 and requires for more effective radioisotopes and ligands. In order to produce a structure most similar to WAY-100635, WAY-100635 derivatives containing a cysteine chelator were designed and confirmed by using in silico (Hyperchem). The novel compounds (7a, 7b, 7c) were prepared in five or 7 steps with yields of 16%, 36% and 42%, respectively and radiolabeled with $[^{99m}Tc(CO)_3(H_2O)_3]^{+}$. The labeling yield was 99% for all the newly synthesized compounds. [$^{99m}Tc(CO)_3$]- WAY-100635 derivatives show a neutral charge which were confirmed by paper electrophoresis.

• Korean Journal of Clinical Pharmacy
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• v.11 no.2
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• pp.89-96
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• 2001

Ziprasidone is equally effective as haloperidol in treating schizophrenia with fewer side effects and drug interactions. Ziprasidone is an atypical antipsychotic agent and works by blocking serotonin and dopamine receptors in the central nervous system, specifically 5-HT2A and D2 receptors. Low anticholinergic side-effects and low EPS would recommend the drug for use in the elderly. Ziprasidone inhibits reuptake of norepinephrine and serotonin at neurojunction sites in vitro, indicating a potential efficacy for depression and negative symptoms which often follow after exacerbation of schizophrenia. Patients with recent acute myocardial infarction and uncompensated heart failure are contraindicated to the drug due to a possibility of QT prolongation. Although ziprasidone is metabolized by cytochrome P450 3A4, there is no significant drug interaction with the drugs that induce or inhibit the isoenzyme. Ziprasidone is safe with coadministration of lithium and there has been no significant drug interaction reported with oral birth control pills.

• Journal of Pharmaceutical Investigation
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• v.39 no.5
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• pp.327-331
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• 2009

5-HT$_{2C}$ receptors have been considered as therapeutic targets for the treatment of various central nervous system disorders such as depression, anxiety, epilepsy, schizophrenia and sleep disorders. We chemically synthesized KKHQ80109 (K09) and KKHQ80114 (K14), selective 5-HT$_{2C}$ agonists, with the purpose of developing therapeutic agents for the treatment of obesity. The objective of this work is to investigate pharmacokinetic parameters and bioavailability of K09 and K14 in rats given orally or intravenously. Oral administration of 20 mg/kg K09 results in 4.11 hr of the terminal half-life and 89.16 ng/mL of C$_{max}$ at 5.00 hr (T$_{max}$). The terminal half-life of K14 was 3.83 hr with 215.81 ng/mL of C$_{max}$ at 3.33 hr (T$_{max}$) after oral dosing of 20 mg/kg K14, indicating that K14 is more rapidly absorbed than K09. Bioavailability showed 0.17-0.21 for K09 and 0.19-0.23 for K14. Urinary excretion of parent K09 and K14 was less than 1%, indicating that K09 and K14 undergo very extensive hepatic metabolism.

• BMB Reports
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• v.46 no.6
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• pp.295-304
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• 2013

Extracellular acidification occurs not only in pathological conditions such as inflammation and brain ischemia, but also in normal physiological conditions such as synaptic transmission. Acid-sensing ion channels (ASICs) can detect a broad range of physiological pH changes during pathological and synaptic cellular activities. ASICs are voltage-independent, proton-gated cation channels widely expressed throughout the central and peripheral nervous system. Activation of ASICs is involved in pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. Therefore, ASICs emerge as potential therapeutic targets for manipulating pain and neurological diseases. The activity of these channels can be regulated by many factors such as lactate, $Zn^{2+}$, and Phe-Met-Arg-Phe amide (FMRFamide)-like neuropeptides by interacting with the channel's large extracellular loop. ASICs are also modulated by G protein-coupled receptors such as CB1 cannabinoid receptors and 5-$HT_2$. This review focuses on the physiological roles of ASICs and the molecular mechanisms by which these channels are regulated.