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1.
Yinghua Yu Yizhen Wu Craig Patch Zhixiang Wu Alexander Szabo Duo Li Xu-Feng Huang 《The Journal of nutritional biochemistry》2013,24(7):1349-1358
Low levels of docosahexaenoic acid (DHA) have been linked to a number of mental illnesses such as memory loss, depression and schizophrenia. While supplementation of DHA is beneficial in improving memory and cognition, the influence of dietary fats on the neurotransmitters and receptors involved in cognitive function is still not known. The aim of this study was to investigate serotonin receptor (5-HT1A and 5-HT2A), cannabinoid receptor (CB1) and gamma-aminobutyric acid type A (GABAA) receptor binding densities in the brain of male rats fed a high-saturated-fat (HF) diet, as well as the effect of DHA supplementation on HF diet. Alterations of these receptors in the post-mortem rat brain were detected by [3H]-WAY-100635, [3H]-ketanserin, [3H]-CP-55,940 and [3H]-muscimol binding autoradiography, respectively. In the hippocampus, the 5-HT1A, CB1 and GABAA receptor binding densities significantly increased in response to an HF diet, while in the hypothalamus, 5-HT1A and CB1 binding densities significantly increased in HF-fed rats. Importantly, DHA supplementation prevented the HF-induced increase of receptors binding density in the hippocampus and hypothalamus. Furthermore, DHA supplementation attenuated 5-HT2A receptor binding density in the caudate putamen, anterior cingulate cortex and medial mammillary nucleus, which was also increased in HF group. This study showed that an HF diet increased 5-HT1A, 5-HT2A, CB1 and GABAA receptor binding densities in the brain regions involved in cognitive function and that dietary DHA can attenuate such alterations. These findings provide insight into the mechanism by which DHA supplementation ameliorates reduced cognitive function associated with an HF diet. 相似文献
2.
Soria-Fregozo C Pérez-Vega MI González-Burgos I Feria-Velasco A Beas-Zárate C 《Neurochemical research》2008,33(11):2350-2357
The 5-HTergic system and particularly 5-HT2A receptors have been involved in prefrontal cognitive functions, but the underlying mechanisms by which the serotonin (5-HT)
system modulates these processes are still unclear. In this work, the effects of prefrontal 5-HTergic denervation on the density
and expression levels of 5-HT2A receptors were evaluated by immunohistochemical and molecular biology studies in the prefrontal cortex (PFC). The [3H]-Ketanserin binding study revealed an increase in the Bmax, along with no change in the binding affinity (KD) for 5-HT2A receptors. The increase in PFC of 5-HT2A receptor density in response to denervation was accompanied by increase in 5-HT2A receptor mRNA and protein levels. This increase in the number of 5-HT2A receptors may be interpreted as an adaptive plastic change, i.e., hypersensitivity; resulting from the selective pharmacological
lesion of the raphe-proceeding 5-HTergic fibers to the PFC. Based on previous evidence, this could be strongly related to
the abnormal expression of short-term memory. 相似文献
3.
Inactivation of 5-HT1A and [3H]5-HT binding sites by N-Ethoxycarbonyl-2-ethoxy-1, 2-dihydro-quinoline (EEDQ) was studied in regions of rat brain. After exposure to EEDQ (4 mg/kg body wt.) for 7 days, it is observed that the density of 5-HT1 receptor sites was decreased by nearly 20% in both cortex and hippocampus. The decrease, however, in 5-HT1A sites was more significant (70%) in both the regions. The affinity of [3H]5-HT to 5-HT1 sites was decreased significantly in both cortex and hippocampus after exposure to EEDQ, without affecting the Kd of 5-HT1A sites. Displacement studies suggested that EEDQ has high affinity to 5-HT1 sites with a Ki of 42.9 ± 2.4 nM. After exposure neither basal nor 5-HT stimulated adenylyl cyclase activity was changed in cortex. The results of this study suggest that EEDQ decreases the density of 5-HT1 and 5-HT1A receptor sites but does not cause functional downregulation of these sites in rat brain. 相似文献
4.
《Bioorganic & medicinal chemistry》2020,28(3):115262
The serotonin 5-HT7 G protein-coupled receptor (GPCR) is a proposed pharmacotherapeutic target for a variety of central and peripheral indications, albeit, there are no approved drugs selective for binding 5-HT7. We previously reported that a lead analog based on the 5-substituted-N,N-disubstituted-1,2,3,4-tetrahydronaphthalen-2-amine (5-substituted-2-aminotetralin, 5-SAT) scaffold binds with high affinity at the 5-HT7 GPCR, and can treat symptoms of autism in mouse models; subsequently, the lead was found to have high affinity at the 5-HT1A GPCR. Herein, we report the synthesis of novel 5-SAT analogs to develop a 3-dimensional quantitative structure—affinity relationship (3D-QSAR) at the human 5-HT7 receptor for comparison with similar studies at the highly homologous 5-HT1A receptor. We report 35 new 5-SAT ligands, some with very high affinity (Ki ≤ 1 nM) and stereoselectivity at 5-HT7 + or 5-HT1A receptors, several with modest selectivity (up to 12-fold) for binding at 5-HT7, and, several ligands with high selectivity (up to 40-fold) at the 5-HT1A receptor. 3D-QSAR results indicate that steric extensions at the C(5)-position improve selectivity for the 5-HT7 over 5-HT1A receptor, while steric and hydrophobic extensions at the chiral C(2)-amino position impart 5-HT1A selectivity. In silico receptor homology modeling studies, supplemented with molecular dynamics simulations and binding free energy calculations, were used to rationalize experimentally-determined receptor selectivity and stereoselective affinity results. The data from these studies indicate that the 5-SAT chemotype, previously shown to be safe and efficacious in rodent paradigms of neurodevelopmental and neuropsychiatric disorders, is amenable to structural modification to optimize affinity at serotonin 5-HT7 vs. 5-HT1A GPCRs, as may be required for successful clinical translation. 相似文献
5.
5-HT1A receptors are involved in the regulation of various behaviors and the mechanism of action of anxiolytics and antidepressants. It is rather difficult to study the expression of the 5-HT1A receptor gene in the brain because of the low concentration of its mRNA. A method developed for quantitating the level of 5-HT1A receptor gene expression in brain structures involves estimation of the copy number for contaminant genomic DNA, the cDNA of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene (a housekeeping gene), and the 5-HT1A receptor gene cDNA in a cDNA preparation. To estimate the GAPDH and 5-HT1A receptor cDNA copy numbers, the fluorescent intensity of the corresponding PCR products is calibrated using genomic DNA standards of known concentrations. The expression of the 5-HT1A receptor gene is corrected for the content of contaminant genomic DNA and presented as a 5-HT1A receptor cDNA copy number per 100 copies of the GAPDH cDNA. The method was used to demonstrate for the first time that expression of the 5-HT1A receptor gene is increased in the frontal cortex and the amygdala of mice knocked-out in the monoamine oxidase A gene. 相似文献
6.
《Life sciences》1995,57(12):A141-A146
The thermodynamic parameters ΔG° , ΔH° and Δs° of the binding equilibrium of serotonin to 5-HT1A, 5-HT2A and 5-HT3 rat-brain membrane receptors have been determined by means of affinity constant measurements at six temperatures in the range 0 –35 ° C and van't Hoff plots. At variance with 5-HT1A and 5-HT3, the binding at the 5-HT2A receptors is strongly endothermic and entropy-driven. Comparison with the results obtained by other authors on 5-HT2A receptors in rats and humans suggests that the observed differences can be explained by a single amino acid difference in the receptor sequence between these two species. 相似文献
7.
Zoe Barclay Louise Dickson Derek Robertson Melanie Johnson Pamela Holland Roberta Rosie Liting Sun Helen Jerina Eve Lutz Sue Fleetwood-Walker Rory Mitchell 《Cellular signalling》2013,25(4):814-821
The 5-HT2A receptor (5-HT2AR) is implicated in psychotropic changes within the central nervous system (CNS). A number of polymorphisms have been reported in the 5-HT2AR gene; one of these results in a non-synonymous change, H452Y, in the carboxy-terminal tail of the receptor protein. The minor allele (9% occurrence) has been statistically associated with CNS dysfunction such as impaired memory processing and resistance to neuroleptic treatment in schizophrenic patients. We investigated the impact of H452Y mutation of the 5-HT2AR expressed in COS7 cells on distinctly coupled intracellular signalling pathways from the receptor, focusing on the heterotrimeric G protein-independent phospholipase D (PLD) pathway, compared to the conventional Gq/11-linked phospholipase C (PLC) pathway. The H452Y mutation selectively attenuated PLD signalling, which as in the wild-type receptor, was mediated by a molecular complex involving PLD1 docked to the receptor's carboxy-terminal tail domain. Co-immunoprecipitation and GST-fusion protein experiments revealed that the H452Y mutation selectively reduced PLD1 binding to the receptor. Experiments with blocking peptides to mimic short sections of the 5-HT2AR tail sequence revealed that the peptide spanning residue 452 strongly reduced PLD but not PLC responses of the receptor. Similar observations were made when assessing both PLD responses and PLD-dependent cellular proliferation elicited by activation of 5-HT2ARs natively expressed in MCF-7 cells. Overall these findings indicate that the H452Y polymorphic variant of the 5-HT2AR displays selective disruption of its PLD signalling pathway. This may potentially play a role in the CNS dysfunction associated with the H452Y allele of the 5-HT2AR. 相似文献
8.
Euna Yoo Juhee Yoon Ae Nim Pae Hyewhon Rhim Woo-Kyu Park Jae Yang Kong Hea-Young Park Choo 《Bioorganic & medicinal chemistry》2010,18(4):1665-1675
A novel series of 5-HT2A ligands that contain a (phenylpiperazinyl-propyl)arylsulfonamides skeleton was synthesized. Thirty-seven N-(cycloalkylmethyl)-4-methoxy-N-(3-(4-arylpiperazin-1-yl)propyl)-arylsulfonamide and N-(4-(4-arylpiperazin-1-yl)butan-2-yl)-arylsulfonamide compounds were obtained. The binding of these compounds to the 5-HT2A, 5-HT2C, and 5-HT7 receptors was evaluated. Most of the compounds showed IC50 values of less than 100 nM and exhibited high selectivity for the 5-HT2A receptor. Among the synthesized compounds, 16a and 16d showed good affinity at 5-HT2A (IC50 = 0.7 nM and 0.5 nM) and good selectivity over 5-HT2C (50–100 times) and 5-HT7 (1500–3000 times). 相似文献
9.
Ryan T. Strachan Douglas J. Sheffler Belinda Willard Michael Kinter Janna G. Kiselar Bryan L. Roth 《The Journal of biological chemistry》2009,284(9):5557-5573
The 5-hydroxytryptamine 2A (5-HT2A) receptor is a member of the
G protein-coupled receptor superfamily (GPCR) and plays a key role in
transducing a variety of cellular signals elicited by 5-hydroxytryptamine in
both peripheral and central tissues. Despite its broad physiological
importance, our current understanding of 5-HT2A receptor regulation
is incomplete. We recently reported the novel finding that the multifunctional
ERK effector ribosomal S6 kinase 2 (RSK2) physically interacts with the
5-HT2A receptor third intracellular (i3) loop and modulates
receptor signaling (Sheffler, D. J., Kroeze, W. K., Garcia, B. G., Deutch, A.
Y., Hufeisen, S. J., Leahy, P., Bruning, J. C., and Roth, B. L. (2006)
Proc. Natl. Acad. Sci. U. S. A. 103, 4717–4722). We report here
that RSK2 directly phosphorylates the 5-HT2A receptor i3 loop at
the conserved residue Ser-314, thereby modulating 5-HT2A receptor
signaling. Furthermore, these studies led to the discovery that RSK2 is
required for epidermal growth factor-mediated heterologous desensitization of
the 5-HT2A receptor. We arrived at these conclusions via multiple
lines of evidence, including in vitro kinase experiments, tandem mass
spectrometry, and site-directed mutagenesis. Our findings were further
validated using phospho-specific Western blot analysis, metabolic labeling
studies, and whole-cell signaling experiments. These results support a novel
regulatory mechanism in which a downstream effector of the ERK/MAPK pathway
directly interacts with, phosphorylates, and modulates signaling of the
5-HT2A serotonin receptor. To our knowledge, these findings are the
first to demonstrate that a downstream member of the ERK/MAPK cascade
phosphorylates a GPCR as well as mediates cross-talk between a growth factor
and a GPCR.The 5-HT2A
2receptor plays a key
role in transducing a variety of cellular signals elicited by 5-HT in both
peripheral and central tissues
(75). These include the
following: 1) platelet aggregation
(1); 2) vascular and
nonvascular smooth muscle contraction
(2); 3) cognitive processes
underlying working memory (3);
4) modulating sensory processing in the cortex
(4); and 5) mediating the
actions of most, but not all, hallucinogens that act as 5-HT2A
receptor agonists (5,
6). Moreover, dysregulation of
the 5-HT2A receptor has been linked to the etiology of several
psychiatric disorders, including depression, anxiety, and schizophrenia, thus
highlighting the importance of gaining a more thorough understanding of the
precise regulation of 5-HT2A receptors
(7).The 5-HT2A receptor belongs to the GPCR superfamily that
encompasses molecular targets for an extreme diversity of endogenous and
exogenous ligands that are essential for nearly every physiological process
(8). Extensive studies focusing
on the G protein-coupled receptor kinase-arrestin pathway and the second
messenger-dependent protein kinase (cAMP-dependent protein kinase and protein
kinase C (PKC)) pathways suggest that direct GPCR phosphorylation remains the
predominant mechanism for rapidly attenuating the signaling of many GPCRs
(9,
10). Additional kinases have
also been shown to phosphorylate GPCRs, and it is likely that many yet to be
discovered kinases regulate GPCR signaling
(11).Several studies have demonstrated that PKC modulates 5-HT2A
receptor signaling in vivo and in vitro. Our early studies
(12) showed that activation of
PKC by phorbol dibutyrate inhibited 5-HT2A-mediated signaling. Many
subsequent studies in a variety of cellular contexts have replicated these
observations
(13–18).
In addition to PKC, recent reports suggest that calmodulin-dependent protein
kinase II and G protein-coupled receptor kinase 2/3 regulate 5-HT2A
signaling (18,
19), although the role of G
protein-coupled receptor kinases is cell-specific
(20). From these prior studies
it is clear that selected kinases modulate 5-HT2A receptor
function, although the site(s) of action and their mechanisms remain
unknown.Recently we discovered that RSK2, a downstream effector of the ERK/MAPK
pathway, regulates the signaling of several GPCRs, including
5-HT2A, P2Y-purinergic, PAR-1-thrombinergic,
β1-adrenergic receptor, and bradykinin-B receptors
(21). RSK2 is a well
characterized member of the RSK family of multifunctional ERK effectors
(RSK1–4), and RSK2 has been shown to phosphorylate a wide variety of
cytoplasmic and nuclear proteins
(22). We
(21) recently showed that RSK2
interacts with the 5-HT2A i3 loop within a conserved region
containing an RSK2-like consensus phosphorylation motif
(275RAKLAS280)
(23). Importantly, RSK2
modulated 5-HT2A receptor signaling independent of changes in
5-HT2A receptor subcellular distribution, global G protein
function, and without altering the expression of any genes known to be
involved in serotonergic signal transduction. Our findings implied that RSK2
acts proximal to receptor activation, at the level of receptor-G protein
coupling, perhaps via direct phosphorylation of 5-HT2A
receptors.Here we provide multiple lines of evidence demonstrating that activated
RSK2 phosphorylates the 5-HT2A receptor i3 loop at the conserved
residue Ser-314. We show that mutation of Ser-314 renders the
5-HT2A receptor insensitive to RSK2 regulation, thereby resulting
in increased signaling mirroring observations in
RSK2–/– fibroblasts
(21). To our knowledge this is
the first report that a downstream member of the ERK/MAPK cascade
phosphorylates a GPCR. Moreover, these studies uncovered a novel regulatory
mechanism whereby RSK2 is required for EGF-mediated heterologous
desensitization of the 5-HT2A receptor. These data support the
intriguing notion that 5-HT2A receptor responsiveness in cells is
influenced by receptor tyrosine kinase (RTK) activation.Because null mutations of RSK2 lead to Coffin-Lowry syndrome, which is
characterized by mental retardation, cardiovascular disorders, and a
schizophrenia-like psychosis
(24), these findings may
explain, in part, some of the clinical manifestations of this syndrome. 相似文献
10.
A. Gandhimathi 《Journal of biomolecular structure & dynamics》2016,34(5):952-970
The serotonin receptors, also known as 5-hydroxytryptamine (5-HT) receptors, are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels found in the central and peripheral nervous systems. GPCRs have a characteristic feature of activating different signalling pathways upon ligand binding and these ligands display several efficacy levels to differentially activate the receptor. GPCRs are primary drug targets due to their central role in several signal transduction pathways. Drug design for GPCRs is also most challenging due to their inherent promiscuity in ligand recognition, which gives rise to several side effects of existing drugs. Here, we have performed the ligand interaction study using the two prominent states of GPCR, namely the active and inactive state of the 5-HT2A receptor. Active state of 5-HT2A receptor model enhances the understanding of conformational difference which influences the ligand-binding site. A 5-HT2A receptor active state model was constructed by homology modelling using active state β2-adrenergic receptor (β2-AR). In addition, virtual screening and docking studies with both active and inactive state models reveal potential small molecule hits which could be considered as agonist-like and antagonist-like molecules. The results from the all-atom molecular dynamics simulations further confirmed that agonists and antagonists interact in different modes with the receptor. 相似文献
11.
《Journal of receptor and signal transduction research》2013,33(1-4):195-221
AbstractTwo complementary approaches, covalent labelling and solubilization, have been used to study the biochemical properties of the central 5-HT1A receptor binding site. We have first designed a photoaffinity ligand containing the structure of 8-OH-DPAT, a potent and specific agonist of 5-HT1A sites. Thus, 8-methoxy-2[N-n-propyl,N-3-(2-nitro-4-azido-phenyl)- aminopropyl]aminotetralin or 8-methoxy-3'-NAP-amino-PAT, was found to displace, in the dark, [3H]8-OH-DPAT from 5-HT1A sites in rat hippocampal membranes with an IC50 of 6.6 nM. Under two cumulative UV irradiations (366 nm, for 20 min at 4°C), 8-methoxy-3-'-NAP-amino-PAT (30 nM) blocked irreversibly 55-60% of 5-HT1A binding sites. This blockade was specific of 5-HT1A sites since the other serotoninergic sites, 5-HT1B, 5-HT2 and also the presynaptic 5-HT3 sites were not affected by the treatment. In addition, the binding of [3H]Spiperone and [3H]7-OH-DPAT to striatal dopamine sites remained unchanged under similar photolysis conditions. The tritiated derivative of the photoaffinity ligand (92 Ci/mmol) was then synthesized for the identification of the covalently bound protein(s). SDS-PAGE of solubilized membranes irradiated in the presence of 20 nM 3H-8-methoxy-3'-NAP-amino-PAT allowed the detection of a 63 kD protein whose labelling appeared specific. Thus, 3H-incorporation into the 63 kD band could be prevented by uM concentrations of 5-HT, 8-OH-DPAT and other selective 5-HT1A ligands such as isapirone. In contrast, the 5-HT2 antagonist ketanserin, norepinephrine and dopamine-related ligands (including 7-OH-DPAT) were ineffective. Direct solubilization of 5-HT1A receptor binding sites was also attempted from rat hippocampal membranes. The best results were obtained using CHAPS (10 mM) plus NaCl (0.2 M), which led to 50 % recovery of 5-HT1A sites in the 100,000 g supernatant. The pharmacological properties and sensitivity to N-ethyl-maleimide and GppNHp of soluble sites appeared near identical to those of membrane-bound 5-HT1A sites. 相似文献
12.
The brain serotonin (5-HT) system has been implicated in the pathophysiology of anxiety, depression, drug addiction, and schizophrenia. 5-HT2A receptors are involved in the mechanisms of stressinduced psychopathology and impulsive behavior. In this work, we investigated the role of 5-HT2A receptors in the autoregulation of the brain 5-HT system. Chronic treatment with DOI, a 5-HT2A receptor agonist (1.0 mg/kg, i.p./14 days), produced a considerable decrease in the number of 5-HT2A receptor-mediated head twitches in AKR/J mice, indicating the desensitization of 5-HT2A receptors. Chronic DOI treatment did not affect the expression of the 5-HT2A receptor gene in the midbrain, hippocampus and frontal cortex. At the same time, an increase in the expression of the gene encoding a key enzyme of 5-HT synthesis, tryptophan hydroxylase-2 (TPH-2), accompanied with an increase in TPH-2 activity and 5-HT levels, and decreased expression of the serotonin transporter (5-HTT) gene were observed in the midbrain of DOI-treated mice. These results provide new evidence of receptor-gene cross-talk in the brain 5-HT system and implication 5-HT2A receptors in the autoregulation of the brain 5-HT system. 相似文献
13.
Trond Brattelid Eirik Qvigstad Lise R. Moltzau Silje V. S. Bekkevold Dagny L. Sandnes Jon Arne K. Birkeland Tor Skomedal Jan-Bj?rn Osnes Ivar Sjaastad Finn Olav Levy 《PloS one》2012,7(9)
A positive inotropic responsiveness to serotonin, mediated by 5-HT4 and 5-HT2A receptors, appears in the ventricle of rats with post-infarction congestive heart failure (HF) and pressure overload-induced hypertrophy. A hallmark of HF is a transition towards a foetal genotype which correlates with loss of cardiac functions. Thus, we wanted to investigate whether the foetal and neonatal cardiac ventricle displays serotonin responsiveness. Wistar rat hearts were collected day 3 and 1 before expected birth (days -3 and -1), as well as day 1, 3, 5 and 113 (age matched with Sham and HF) after birth. Hearts from post-infarction HF and sham-operated animals (Sham) were also collected. Heart tissue was examined for mRNA expression of 5-HT4, 5-HT2A and 5-HT2B serotonin receptors, 5-HT transporter, atrial natriuretic peptide (ANP) and myosin heavy chain (MHC)-α and MHC-β (real-time quantitative RT-PCR) as well as 5-HT-receptor-mediated increase in contractile function ex
vivo (electrical field stimulation of ventricular strips from foetal and neonatal rats and left ventricular papillary muscle from adult rats in organ bath). Both 5-HT4 mRNA expression and functional responses were highest at day -3 and decreased gradually to day 5, with a further decrease to adult levels. In HF, receptor mRNA levels and functional responses reappeared, but to lower levels than in the foetal ventricle. The 5-HT2A and 5-HT2B receptor mRNA levels increased to a maximum immediately after birth, but of these, only the 5-HT2A receptor mediated a positive inotropic response. We suggest that the 5-HT4 receptor is a representative of a foetal cardiac gene program, functional in late foetal development and reactivated in heart failure. 相似文献
14.
Jitesh R. Shah Philip D. Mosier Srinivas Peddi Bryan L. Roth Richard B. Westkaemper 《Bioorganic & medicinal chemistry letters》2010,20(3):935-938
Synthesis, radioligand binding and molecular modeling studies of several 9-aminomethyl-9,10-dihydroanthracene (AMDA) analogs were carried out to determine the extent of the steric tolerance associated with expansion of the tricyclic ring system and amine substitution at 5-HT2A and H1 receptors. A mixture of (7,12-dihydrotetraphene-12-yl)methanamine and (6,11-dihydrotetracene-11-yl)methanamine in a 75–25% ratio was found to have an apparent Ki of 10 nM at the 5-HT2A receptor. A substantial binding affinity for (7,12-dihydrotetraphene-3-methoxy-12-yl)methanamine at the 5-HT2A receptor (Ki = 21 nM) was also observed. Interestingly, this compound was found to have 100-fold selectivity for 5-HT2A over the H1 receptor (Ki = 2500 nM). N-Phenylalkyl-AMDA derivatives, in which the length of the alkyl chain varied from methylene to n-butylene, were found to have only weak affinity for both 5-HT2A and H1 receptors (Ki = 223 to 964 nM). Our results show that large rigid annulated AMDA analogs can be sterically accommodated within the proposed 5-HT2A binding site. 相似文献
15.
Michael R. Pranzatelli 《Neurochemical research》1994,19(3):311-315
To study the early effects of neonatal 5,7-dihydroxytryptamine lesions on 5-hydroxytryptamine1A (5-HT1A) receptors, we measured regional [3H]8-OH-DPAT-labeled 5-HT1A sites in binding assays and compared them to our previous studies of [3H]paroxetine-labeled 5-HT transporter sites during the first month in the same rats. While there were significant time- and dose-dependent effects of 5,7-DHT on 5-HT transporter sites, there were no significant changes in 5-HT1A sites in cortex, hippocampus, diencephalon, brainstem, cerebellum, or spinal cord. 5,7-DHT lesions also did not alter the Ki of Gpp(NH)p at brainstem 5-HT1A sites or the Ki of 5-HT in cortex or brainstem in the presence or absence of GTPS or Gpp(NH)p. There were significant regional differences between the density of 5-HT1A sites and 5-HT transporter sites. The ontogeny of brainstem 5-HT1A sites was a pattern of increases until three weeks postnatal, and 5,7-DHT lesions did not alter the ontogeny of 5-HT1A sites. These data suggest differential plasticity of 5-HT1A and 5-HT transporter binding sites during the first month after neonatal 5,7-DHT lesions. 相似文献
16.
《Comp. Biochem. Physiol. C, Comp. Pharmacol. Toxicol.》1994,107(1):129-141
The ability of the selective 5-HT1A receptor agonist R(+)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) to bind with 5-HT receptor(s) on cultured, identified neurones in Lymnaea stagnalis was examined. The identified neurones studied were from the buccal ganglia and the serotonin-containing cerebral giant cells (CGCs). 5-HT and its agonists were applied from puffer pipettes, whilst 5-HT antagonists were applied in the bathing medium. At 10−3 M, the 5-HT1A agonist, always produced paroxysmal depolarizing shifts (PDS) while at a lower concentration (10−4 M), it always mimicked the effects of 10−3 M 5-HT. 8-OH-DPAT (10−4 M) and 5-HT 10−3 M produced dose-dependent increases in the responses they evoked. At 10−4 M, the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide hydrochloride (m-CPBG), failed to hyperpolarize most of the neurones hyperpolarized by 5-HT. At 10−4 M, the antagonists ketanserin (5-HT2), MDL 72222 (5-HT3), and pindobind-5-HT1A (5-HT1A) consistently abolished spike generation ii spontaneously active neurones. Both ketanserin and MDL 72222 failed to block the actions of 8-OH-DPAT and only partially blocked those of 5-HT, but pindobind-5-HT1A completely, but reversibly,blocked the 8-OH-DPAT effects while greatly reducing those of 5-HT. These results suggest that 5-HT1A receptor subtypes might be involved in the hyperpolarizing responses of the CGCs and their follower motor neurones in the buccal ganglia of Lymnaea stagnalis to 5-HT. The presence of 5-HT1A receptors on these neurones can be considered to correspond with those found in mammals because their pharmacological responses resemble those of mammalian 5-HT1A receptors. 相似文献
17.
Suk Youn Kang Eun-Jung Park Woo-Kyu Park Hyun Jung Kim Daeyoung Jeong Myung Eun Jung Kwang-Seop Song Suk Ho Lee Hee Jeong Seo Min Ju Kim MinWoo Lee Ho-Kyun Han Eun-Jung Son Ae Nim Pae Jeongmin Kim Jinhwa Lee 《Bioorganic & medicinal chemistry letters》2010,20(5):1705-1711
Arylpiperzine-containing pyrrole 3-carboxamide derivatives were synthesized and evaluated as novel antidepressant compounds. The various analogues were efficiently prepared and bio-assayed for binding to 5-HT2A, 5-HT2C receptor, and 5-HT transporter. Based on their in vitro and in vivo activities as well as selectivity over other neurotransmitter receptors and PK profiles, 33 and 34 were identified as lead compounds. Consequently, this pyrrole series of compounds appears to be promising enough to warrant further investigation. 相似文献
18.
《Life sciences》1994,55(6):PL105-PL114
The present studies document marked differences in contractile responsiveness to serotonin in trachea and aorta between guinea pig and rat. For example, the guinea pig trachea and rat aorta markedly contract in response to serotonin via activation of 5-HT2A receptors. In contrast, the rat and guinea pig aorta only modestly contract to serotonin. The availability of 5-HT2A receptor selective cDNA clones from brain of both guinea pig and rat permitted molecular probes to be designed and PCR amplification studies initiated to identify and quantify 5-HT2A receptor specific mRNA in these tissues. For trachea, 3-fold higher concentrations of 5-HT2A receptor specific mRNA were found in guinea pig relative to rat trachea. These data are consistent with the more profound contractile response to serotonin in guinea pig versus rat trachea and suggest that differences in tracheal contractility to serotonin correlate with the density of 5-HT2A receptor mRNA. In contrast, although rat aorta contracted more dramatically to serotonin than guinea pig aorta, rat aorta possessed a similar concentration of 5-HT2A receptor specific mRNA as compared to guinea pig aorta. Thus, for the aorta, differences in the concentration of 5-HT2A receptor mRNA are not sufficient to explain the observed differences in contractility between tissues from guinea pig and rat. These studies documenting 5-HT2A receptor mRNA in rat trachea and guinea pig aorta, two tissues that do not markedly contract in response to serotonin indicate that 5-HT2A receptor mRNA although present, has not resulted in a receptor capable of mediating a contractile response in these tissues. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(7):1664-1667
A set of aporphine analogs related to nantenine was evaluated for antagonist activity at 5-HT2A and α1A adrenergic receptors.With regards to 5-HT2A receptor antagonism, a C2 allyl group is detrimental to activity. The chiral center of nantenine is not important for 5-HT2A antagonist activity, however the N6 nitrogen atom is a critical feature for 5-HT2A antagonism.Compound 12b was the most potent 5-HT2A aporphine antagonist identified in this study and has similar potency to previously identified aporphine antagonists 2 and 3. The ring A and N6 modifications examined were detrimental to α1A antagonism. A slight eutomeric preference for the R enantiomer of nantenine was observed in relation to α1A antagonism. 相似文献
20.
《Journal of receptor and signal transduction research》2013,33(1-4):443-455
AbstractIn order to set up the technique of semi-quantitative in situ hybridisation to detect the serotonin receptor mRNA levels in brain tissue, a panel of three Swiss 3T3 cell clones (named clones 66, 53 and 47) expressing the human 5-HT1A receptor at different densities were used as a model. The clones were generated by limiting dilution from pools of stably transfected cells. In addition membranes were prepared from each clone to perform receptor binding studies. Clones 66, 53, and 47 showed saturable binding for the agonist [3H]-8-OHDPAT, with receptor densities (Bmax) of 227 ± 86, 548 ± 107 and 1505 ± 212 fmol/mg protein respectively, and with corresponding affinity constants (pKd) of 8.8 ± 0.1, 9.1 ± 0.1, and 9.1 ± 0.1 nM, respectively. Northern blot analysis using a specific probe for the 5-HTIA receptor revealed the presence of a single 1.56 kilobase mRNA species in the 5-HT1A receptor clones but not in control cells. In situ hybridisation studies were performed by measuring the 5-HT1A receptor mRNA levels in these three 5-HT1A transfectants using [35S]αCTP labeled riboprobes (sense and anti-sense). The following rank order of receptor mRNA expression was found for clones 66, 53 and 47 respectively: 0.140 ± 0.001, 0.365 ± 0.045 and 0.835 ± 0.115 (relative optical density units). With the sense probe no specific labelling was observed. In conclusion, a positive correlation was found between receptor density (Bmax) and receptor mRNA expression (semi-quantitative in situ hybridisation) using human 5-HT1A receptor clones with different expression levels. 相似文献