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British Journal of Pharmacology Aug 2015The 5-HT3 receptor is a member of the pentameric ligand-gated ion channel family and is pharmacologically targeted to treat irritable bowel syndrome and nausea/emesis....
BACKGROUND AND PURPOSE
The 5-HT3 receptor is a member of the pentameric ligand-gated ion channel family and is pharmacologically targeted to treat irritable bowel syndrome and nausea/emesis. Furthermore, many antidepressants elevate extracellular concentrations of 5-HT. This study investigates the functional consequences of exposure of recombinant 5-HT3 A receptors to agonists and antagonists.
EXPERIMENTAL APPROACH
We used HEK cells stably expressing recombinant 5-HT3 A receptors and the ND7/23 (mouse neuroblastoma/dorsal root ganglion hybrid) cell line, which expresses endogenous 5-HT3 receptors. Surface expression of recombinant 5-HT3 A receptors, modified to contain the bungarotoxin (BTX) binding sequence, was quantified using fluorescence microscopy to image BTX-conjugated fluorophores. Whole cell voltage-clamp electrophysiology was used to measure the density of current mediated by 5-HT3 A receptors.
KEY RESULTS
5-HT3 A receptors were up-regulated by the prolonged presence of agonists (5-HT and m-chlorophenylbiguanide) and antagonists (MDL-72222 and morphine). The up-regulation of 5-HT3 A receptors by 5-HT and MDL-72222 was time- and concentration-dependent but was independent of newly translated receptors. The phenomenon was observed for recombinant rodent and human 5-HT3 A receptors and for endogenous 5-HT3 receptors in neuronal ND7/23 cells.
CONCLUSIONS AND IMPLICATIONS
Up-regulation of 5-HT3 A receptors, following exposure to either agonists or antagonists suggests that this phenomenon may occur in response to different therapeutic agents. Medications that elevate 5-HT levels, such as the antidepressant inhibitors of 5-HT reuptake and antiemetic inhibitors of 5-HT3 receptor function, may both raise receptor expression. However, this will require further investigation in vivo.
Topics: Animals; Biguanides; Cell Line, Tumor; HEK293 Cells; Humans; Mice; Morphine; Rats; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tropanes; Up-Regulation
PubMed: 25989383
DOI: 10.1111/bph.13197 -
Journal of Pharmacological Sciences Jan 2008Repeated administration of psychostimulants elicits a progressive enhancement of locomotor activity known as behavioral sensitization. Central dopamine (DA) neurons play... (Review)
Review
Repeated administration of psychostimulants elicits a progressive enhancement of locomotor activity known as behavioral sensitization. Central dopamine (DA) neurons play key roles as the neural substrates mediating behavioral sensitization, but the role of the serotonin (5-HT) system in the sensitization is not fully elucidated. We have recently demonstrated that osemozotan, a specific 5-HT(1A)-receptor agonist, and ritanserin, a 5-HT(2)-receptor antagonist, inhibited the expression and development of both methamphetamine- and cocaine-induced behavioral sensitization in mice and that these drugs attenuated the maintenance of behavioral sensitization of methamphetamine, but not that of cocaine. We also found that azasetron, a 5-HT(3)-receptor antagonist, inhibited the expression and development of the sensitization induced by methamphetamine and cocaine, respectively. Neurochemical studies using a microdialysis technique showed that repeated methamphetamine enhanced the methamphetamine-induced increase in 5-HT release in the prefrontal cortex. The sensitization of 5-HT release in methamphetamine-treated mice was attenuated by osemozotan and ritanserin. These findings suggest that the 5-HT system plays an important role in methamphetamine- and cocaine-induced behavioral sensitization in mice and imply that 5-HT(1A)-receptor agonists and 5-HT(2)-receptor antagonists may have a potential therapeutic value for the treatment of methamphetamine abuse or psychosis.
Topics: Amphetamine-Related Disorders; Animals; Behavior, Animal; Brain; Bridged Bicyclo Compounds, Heterocyclic; Central Nervous System Stimulants; Cocaine; Cocaine-Related Disorders; Dioxanes; Dioxoles; Disease Models, Animal; Ligands; Methamphetamine; Mice; Motor Activity; Oxazines; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT3 Receptor Antagonists; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 18198473
DOI: 10.1254/jphs.fm0070121 -
Japanese Journal of Pharmacology Jun 2001Binding affinities of serotonin (5-HT)-receptor antagonists and agonists at human recombinant alpha1-adrenoceptor subtypes (alpha1a-, alpha1b- and alpha1d-subtypes) were...
Binding affinities of serotonin (5-HT)-receptor antagonists and agonists at human recombinant alpha1-adrenoceptor subtypes (alpha1a-, alpha1b- and alpha1d-subtypes) were examined and compared with the functional affinities obtained in rat caudal artery (alpha1A-subtype), dog carotid artery (alpha1B-subtype) and rat thoracic aorta (alpha1D-subtype). Most of the 5-HT-receptor antagonists and agonists tested showed relatively high affinity to three alpha1-adrenoceptor subtypes. The highest affinity close to 1 nM was seen for NAN-190 (5-HT1A antagonist) in binding and functional studies. 5-Methylurapidil (5-HT1A agonist) and BMY7378 (5-HT1A agonist) showed, respectively, alpha1a(alpha1A)- or alpha1d(alpha1D)-subtype selectivity in both binding and functional affinities, but spiperone (5-HT2A antagonist) showed alpha1b-selectivity only in binding affinity. Functional affinity of ritanserin (5-HT2A antagonist) to the alpha1B-subtype was approximately 500-fold lower than that of affinity to the alpha1b-subtype. The present results show that many 5-HT-receptor antagonists and agonists have high affinity to alpha1-adrenoceptors, but suggest that there is deviation between their functional affinities and binding affinities for some drugs.
Topics: Animals; Aorta, Thoracic; Carotid Arteries; Dogs; Humans; Male; Organ Culture Techniques; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1; Recombinant Proteins; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 11459121
DOI: 10.1254/jjp.86.189 -
Drug and Alcohol Dependence Jul 2012Psychostimulant abuse continues to present legal, socioeconomic and medical challenges as a primary psychiatric disorder, and represents a significant comorbid factor in... (Review)
Review
Psychostimulant abuse continues to present legal, socioeconomic and medical challenges as a primary psychiatric disorder, and represents a significant comorbid factor in major psychiatric and medical illnesses. To date, monotherapeutic drug treatments have not proven effective in promoting long-term abstinence in psychostimulant abusers. In contrast to clinical trials utilizing monotherapies, combinations of dopamine (DA) agonists and selective 5-HT(3), 5HT(2A/2C), or NK(1) antagonists have shown robust efficacy in reversing behavioral and neurobiological alterations in animal models of psychostimulant abuse. One important temporal requirement for these treatments is that the 5-HT or NK(1) receptor antagonist be given at a critical time window after DA agonist administration. This requirement may reflect a necessary dosing regimen towards normalizing underlying dysfunctional neural circuits and "addiction memory" states. Indeed, chronic psychostimulant abuse can be conceptualized as a consolidated form of dysfunctional memory maintained by repeated drug- or cue-induced reactivation of neural circuit and subsequent reconsolidation. According to this concept, the DA agonist given first may reactivate this memory circuit, thereby rendering it transiently labile. The subsequent antagonist is hypothesized to disrupt reconsolidation necessary for restabilization, thus leading progressively to a therapeutically-mediated abolishment of dysfunctional synaptic plasticity. We propose that long-term abstinence in psychostimulant abusers may be achieved not only by targeting putative mechanistic pathways, but also by optimizing drug treatment regimens designed to disrupt the neural processes underlying the addicted state.
Topics: Animals; Behavior Therapy; Central Nervous System Sensitization; Central Nervous System Stimulants; Humans; Ondansetron; Rats; Self Administration; Serotonin Antagonists; Substance-Related Disorders
PubMed: 22356892
DOI: 10.1016/j.drugalcdep.2012.01.021 -
Scientific Reports Jan 2017Social interactions leading to dominance hierarchies often elicit psychological disorders in mammals including harassment and anxiety. Here, we demonstrate that this...
Social interactions leading to dominance hierarchies often elicit psychological disorders in mammals including harassment and anxiety. Here, we demonstrate that this sequence also occurs in an invertebrate, the crayfish Procambarus clarkii. When placed in the restricted space of an aquarium, crayfish dyads generally fight until one of the opponents suddenly escapes, thereafter clearly expressing a submissive behaviour. Nevertheless, the winner frequently keeps on displaying excessive aggressive acts, having deleterious consequences in losers and interpreted as harassment behaviour. We indeed observed that, contrary to winners, losers expressed anxiety-like behaviour (ALB) in correlation with the stress intensity they suffered during the harassment period mainly. Injections of an anxiolytic abolished ALB, confirming its homology with anxiety. A serotonin (5-HT) antagonist had the same effect, suggesting a role for 5-HT, whose brain concentrations increased much more in losers than in winners. Our findings suggest that the bases of harassment and of its anxiogenic consequences have emerged very early during evolution, and emphasize crayfish as an unexpected but potentially fruitful model for the study of these social disorders.
Topics: Animals; Anxiety; Astacoidea; Behavior, Animal; Brain; Chlordiazepoxide; Chromatography, High Pressure Liquid; Serotonin; Serotonin Antagonists; Social Dominance
PubMed: 28045136
DOI: 10.1038/srep39935 -
ACS Chemical Neuroscience Sep 2016Several pharmacophore models have been proposed for 5-HT2A serotonin receptor antagonists. These typically consist of two aromatic/hydrophobic moieties separated by a...
Several pharmacophore models have been proposed for 5-HT2A serotonin receptor antagonists. These typically consist of two aromatic/hydrophobic moieties separated by a given distance from each other, and from a basic amine. Although specified distances might vary, the models are relatively similar in their general construction. Because our preliminary data indicated that two aromatic (hydrophobic) moieties might not be required for such action, we deconstructed the serotonin-dopamine antipsychotic agent risperidone (1) into four smaller structural fragments that were thoroughly examined in 5-HT2A receptor binding and functional (i.e., two-electrode voltage clamp (TEVC) and intracellular calcium release) assays. It was apparent that truncated risperidone analogues behaved as antagonists. In particular, 6-fluoro-3-(1-methylpiperidin-4-yl)benzisoxazole (4) displayed high affinity for 5-HT2A receptors (Ki of ca. 12 nM) relative to risperidone (Ki of ca. 5 nM) and behaved as a potent 5-HT2A serotonin receptor antagonist. These results suggest that multiple aromatic (hydrophobic) moieties are not essential for high-affinity 5-HT2A receptor binding and antagonist activity and that current pharmacophore models for such agents are very much in need of revision.
Topics: Animals; Barium; Calcium; G Protein-Coupled Inwardly-Rectifying Potassium Channels; HEK293 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Ketanserin; Membrane Potentials; Mutation; Oocytes; Protein Binding; Receptor, Serotonin, 5-HT2A; Risperidone; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Tritium; Xenopus laevis
PubMed: 27385190
DOI: 10.1021/acschemneuro.6b00162 -
Drug News & Perspectives Nov 2007Modulating activity at the 5-HT(2C) receptor holds a tremendous amount of therapeutic promise in multiple psychiatric indications. However, the signaling and regulation... (Review)
Review
Modulating activity at the 5-HT(2C) receptor holds a tremendous amount of therapeutic promise in multiple psychiatric indications. However, the signaling and regulation of the 5-HT(2C) receptor is highly complex due to multiple signaling pathways and agonist-directed trafficking of this receptor. Moreover, the 5-HT(2C) receptor is differentially regulated via RNA editing in multiple psychiatric disorders and following either pharmacological or environmental manipulation. Direct and indirect data suggest that both agonists and antagonists may provide benefits in several disorders. The current review highlights the underlying complexities of this area and provides the rationale for using 5-HT(2C) agonists in the treatment of both schizophrenia and depressive disorders.
Topics: Animals; Depressive Disorder; Drug Design; Humans; Receptor, Serotonin, 5-HT2C; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction
PubMed: 18176661
DOI: 10.1358/dnp.2007.20.9.1162244 -
PloS One 2013A wide body of evidence suggests that 5-HT7 receptors are implicated in a variety of central nervous system functions, including control of learning and memory...
A wide body of evidence suggests that 5-HT7 receptors are implicated in a variety of central nervous system functions, including control of learning and memory processes. According to recent preclinical data, the selective blockade of these receptors may be a potential target for cognitive improvement in schizophrenia. The first aim of the present study was to evaluate the effects of the selective 5-HT7 receptor antagonist, SB-269970, and the antipsychotic drug with a high affinity for 5-HT7 receptors, amisulpride, on ketamine-induced deficits in attentional set-shifting and novel object recognition tasks in rats. Because the role of 5-HT7 receptor blockade in ameliorating positive and negative symptoms of schizophrenia remains equivocal, the second aim of these experiments was to examine the effectiveness of SB-269970 and amisulpride in reversing ketamine-induced deficits in prepulse inhibition of the startle reflex and in social interaction test in rats. The study revealed that acute administration of SB-269970 (1 mg/kg) or amisulpride (3 mg/kg) ameliorated ketamine-induced cognitive inflexibility and novel object recognition deficit in rats. Both compounds were also effective in attenuating ketamine-evoked disruption of social interactions. In contrast, neither SB-269970 nor amisulpride affected ketamine-disrupted prepulse inhibition or 50 kHz USVs accompanying social behaviour. In conclusion, antagonism of 5-HT7 receptors may represent a useful pharmacological approach in the treatment of cognitive deficits and some negative symptoms of schizophrenia.
Topics: Amisulpride; Animals; Ketamine; Male; Phenols; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Sulfonamides; Sulpiride
PubMed: 23776692
DOI: 10.1371/journal.pone.0066695 -
Journal of Medicinal Chemistry Nov 2023The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple...
The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HTR antagonism and interaction with 5-HTR were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HTR antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. , but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HTR/5-HTR/MAO-B in AD.
Topics: Rats; Animals; Serotonin; Cryoelectron Microscopy; Receptors, Serotonin; Serotonin Antagonists; Alzheimer Disease; Monoamine Oxidase; Cognition; Monoamine Oxidase Inhibitors
PubMed: 37797083
DOI: 10.1021/acs.jmedchem.3c01482 -
Zhongguo Yao Li Xue Bao = Acta... Dec 1999One specific example reflecting the complexity of cardiovascular responses induced by serotonin (5-hydroxytryptamine; 5-HT) and the progress achieved in the... (Review)
Review
One specific example reflecting the complexity of cardiovascular responses induced by serotonin (5-hydroxytryptamine; 5-HT) and the progress achieved in the pharmacological characterization of the receptors involved can be illustrated by the effects of 5-HT on the canine external carotid artery bed. Within this framework, it has been shown that the external carotid vasoconstrictor response to 5-HT in the dog is mediated by '5-HT1-like' receptors, which being blocked by the 5-HT1B/1D receptor antagonist GR127935, resemble 5-HT1B/1D (previously called 5-HT1D beta/1D alpha) receptors. It was proposed that these receptors could belong to the 5-HT1B, rather than the 5-HT1D, subtype on the basis of their resistance to blockade by a high dose of ritanserin (a potential 5-HT1D receptor antagonist) and the presence of mRNA for 5-HT1B(5-HT1D beta) receptors, but not for 5-HT1D(5-HT1D alpha) receptors, in vascular smooth muscle. With the advent of subtype-selective antagonists it was subsequently shown that external carotid vasoconstriction to 5-HT and sumatriptan is dose-dependently antagonized by the selective 5-HT1B receptor antagonist SB224289 (2,3,6,7-tetrahydro-1'-methyl-5-[2'-methyl-4' (5-methyl-1,2,4-oxadiazol-3-yl) biphenyl-4-carbonyl] furo [2,3-f] indole-3-spiro-4'-piperidine hydrochloride), whereas the selective 5-HT1D receptor antagonist BRL15572 (1-(3-chlorophenyl)-4-[3,3-diphenyl (2-(S,R) hydroxypropanyl) piperazine] hydrochloride) was ineffective. These findings represent the first in vivo evidence showing that vascular constriction induced by 5-HT and sumatriptan is mediated primarily via 5-HT1B, but not 5-HT1D receptors. The pharmacological profile of these receptors could be similar (isolated human temporal artery and porcine carotid arteriovenous anastomoses) to other putative 5-HT1B receptors mediating vasoconstrictor responses. In view of the putative pathophysiologic role of external carotid (and extracerebral) vasodilation in migraine, the constriction of these blood vessels by sumatriptan via 5-HT1B receptors may be, at least partly, responsible for its therapeutic efficacy in migraine.
Topics: Animals; Carotid Artery, External; Dogs; Humans; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Vasoconstriction
PubMed: 11216445
DOI: No ID Found