共查询到20条相似文献,搜索用时 31 毫秒
1.
Kevin M. Lawrence Jan Falkowski Robin R. Jacobson Roger W. Horton 《Psychopharmacology》1993,110(1-2):235-239
Platelet 5-HT uptake sites were measured in 40 depressed patients and 40 controls using [3H] imipramine binding, defined with desmethylimipramine (DMI) and Na+ dependence, and [3H] paroxetine binding. In control subjects the Bmax of DMI defined [3H] imipramine binding was significantly higher than both Na+ dependent [3H] imipramine (by 30%) and [3H] paroxetine binding (by 22%). The Bmax of Na+ dependent [3H] imipramine and [3H] paroxetine binding did not differ significantly. The Kd of Na+ dependent [3H] imipramine binding was significantly lower than the Kd of DMI defined [3H] imipramine binding. The binding of DMI defined and Na+ dependent [3H] imipramine and [3H] paroxetine did not differ significantly between depressed patients and controls in the total group, in those depressed patients who had never taken antidepressants or in those depressed patients who had been recently with-drawn from antidepressants. This study provides no support for the view that the number of platelet 5-HT uptake sites are reduced in depression. 相似文献
2.
Several reports have shown heterogeneity of [3H]imipramine binding to brain membranes. Recently, a high affinity and 5-HT sensitive [3H]imipramine binding site of protein nature, that was suggested to be identical to the substrate recognition site for 5-HT uptake, was demonstrated. Since most studies on the regulation of the [3H]imipramine binding sites by antidepressants have used desipramine displaceable binding, which is heterogenous in nature and contains binding not related to 5-HT uptake sites, the present report studies the possible effects of chronic (3 weeks) administration of imipramine or norzimeldine (10 mg/kg intraperitoneally twice daily) on 5-HT sensitive [3H]imipramine binding sites. For comparison, desipramine sensitive binding was also studied, as well as the physiological correlate 5-HT uptake. There were no changes in either [3H]imipramine binding or 5-HT uptake after the antidepressant treatment.Supported by the Swedish Medical Research Council
Offprint requests to: J. Marcusson at Dept. of Geriatric Medicine 相似文献
3.
M. F. Poirier A. M. Galzin C. Pimoule H. Schoemaker K. H. Le Quan Bui P. Meyer C. Gay H. Loo S. Z. Langer 《Psychopharmacology》1988,94(4):521-526
Platelet [3H]-5HT uptake, [3H]-imipramine binding and endogenous 5HT levels were measured in healthy volunteers during short-term (20 days) administration of lithium, and following its withdrawal. The V
max of [3H]-5HT uptake was significantly decreased during lithium treatment. Following lithium withdrawal, platelet [3H]-5HT uptake (V
max) remained decreased and was followed by a pronounced rebound effect in some of the subjects for up to 3 months. The affinity constant (K
m) of [3H-5HT uptake was not modified. Binding of tritiated imipramine during the same period and platelet 5HT levels measured till 14 days after withdrawal was not affected by lithium treatment. As lithium is devoid of in vitro effects on both 5HT uptake and imipramine binding, it is concluded that the effects of lithium on the 5HT transporter do not reflect a direct effect on the transporter complex. Our results indicate that lithium-induced changes at the level of 5HT uptake in platelets are not correlated with concomitant variations in platelet 5HT content and can be dissociated from modifications at the level of imipramine binding sites within the macromolecular complex of the 5HT transporter. Moreover, platelet 5HT uptake is apparently modulated by lithium, with a similar pattern in healthy volunteers and in manic-depressive patients. 相似文献
4.
Moshe Rehavi Yitzhak Ittah Phil Skolnick Kenner C. Rice Steven M. Paul 《Naunyn-Schmiedeberg's archives of pharmacology》1982,320(1):45-49
Summary A series of nitro derivatives of imipramine have been prepared by nitration of imipramine. Several of the products, especially 2-nitroimipramine (2) and 2,8-dinitroimipramine (4) were found to be very potent inhibitors of [3H] serotonin uptake and high affinity [3H] imipramine binding in human platelets. In contrast to the parent antidepressant, imipramine, the inhibition of platelet [3H] serotonin uptake and [3H] imipramine binding by the nitro derivatives of imipramine was long-acting and essentially irreversible at low temperatures. These compounds should prove to be valuable tools for subsequent studies on the purification and characterization of the transport protein(s) involved in serotonin uptake and may have novel behavioral and clinical effects. 相似文献
5.
Alain Segonzac Hans Schoemaker Christopher R. Lee Salomon Z. Langer 《Naunyn-Schmiedeberg's archives of pharmacology》1987,336(1):1-4
Summary 5-Methoxytryptoline (5-MeO-TLN, 6-methoxytetrahydro--carboline) inhibits with high affinity [3H]-imipramine binding to the serotonin transporter in platelets. To evaluate whether 5-MeO-TLN is a substrate for the serotonin transporter, the accumulation of [3H]-5-MeO-TLN into rabbit platelets was studied in vitro. At short incubation times (5 min), [3H]-5-MeO-TLN accumulation was temperature-sensitive, but not saturable over a concentration range from 0.06 mol/l to 10 mol/l Moreover, [3H]-5-MeO-TLN uptake was not affected by 100 mol/1 ouabain, its structural analogs tryptoline and 5-hydroxytryptoline, nor by the serotonin uptake inhibitors imipramine and citalopram. After longer incubation times (60 min), [3H]-5-MeO-TLN accumulation at O°C approached that seen at 37°C and temperature-sensitive [3H]-5-MeO-TLN uptake could no longer be observed. It is concluded that temperature-sensitive accumulation of [3H]-5-MeO-TLN is not mediated by the serotonin transporter and most likely represents a passive, diffusional process, the rate of which is temperature-dependent. The present studies thus confirm the hypothesis that 5-MeO-TLN affects [3H]-imipramine binding in platelets through a competitive mechanism and not via an allosteric interaction mediated through the substrate recognition site of the macromolecular complex of the serotonin transporter.
Send offprint requests to S. Z. Langer at the above address 相似文献
6.
Graciela Piñeyro Lyne Deveault Pierre Blier Trevor Dennis Claude de Montigny 《Naunyn-Schmiedeberg's archives of pharmacology》1995,351(2):111-118
In the present study, in vivo extracellular unitary recordings, in vitro [3H]5-HT uptake and [3H]cyanoimipramine binding assays were used to assess the effect of acute and prolonged administration of the putative antidepressant tianeptine, on the 5-hydroxytryptamine (5-HT) transporter. Microiontophoretic application of tianeptine onto dorsal hippocampus CA3 pyramidal neurons, as well as its intravenous administration (2 mg/kg), increased their firing frequency. Following intracerebroventricular administration of 5,7-dihydroxytryptamine, the activation induced by the microiontophoretic application of tianeptine remained unchanged, thus suggesting that the 5-HT carrier is not involved in this effect. Furthermore, in spite of its activating effect on CA3 pyramidal neuron firing frequency, the intravenous administration of tianeptine did not alter the time of recovery of these neurons from microiontophoretic applications of 5-HT, an index of 5-HT uptake activity. In keeping with this observation, the acute administration of tianeptine did not change the effectiveness of the 5-HT reuptake blocker paroxetine (1 mg/kg, i.v.) in prolonging the suppressant effect of microiontophoretically-applied 5-HT. However, in rats that had received tianeptine for 14 days (20 mg/kg/day, s.c.), the recovery time from the suppressant effect of microiontophoretic applications of 5-HT was reduced by 40% and the effectiveness of paroxetine (1 mg/kg, i.v.) was decreased. These effects were no longer observed following a 48 h washout period. In a second series of experiments, the ability of tianeptine to interfere with the uptake blocking capacity of paroxetine was assessed in vitro, using hippocampal slices obtained from rats that had been treated with tianeptine for 14 days (20 mg/kg/day, s.c.; by minipump). The effectiveness of paroxetine to block [3H]5-HT uptake was unchanged in slices obtained from rats still bearing the osmotic minipump at the time of the sacrifice, as well as from those which had undergone a 48 h washout period. To assess whether prolonged administration of tianeptine would induce adaptive changes on 5-HT uptake sites, [3H]cyanoimipramine-binding parameters were measured following a 48 h washout period. Affinity values remained unchanged while density values were significantly increased in cortex (+22%) but not in hippocampus (+12%). It is concluded that, i) the activation of CA3 pyramidal neurons observed following acute tianeptine administration cannot be attributed to its 5-HT uptake enhancing properties and ii) the prolonged administration of tianeptine induces adaptive changes on cortical but not on hippocampal 5-HT transporters.Deceased 10 May 1994 相似文献
7.
B. Kenneth Koe Lorraine A. Lebel Carol B. Fox John E. Macor 《Drug development research》1992,25(1):67-74
3-(1,2,5,6-Tetrahydro-4-pyridyl)-5-pyrrolo[3,2-b]pyridone, CP-93, 129, is a selective agonist ligand for 5-HT1B receptors. High affinity binding sites of [3H]CP-93, 129 were found in rat whole brain membranes, which showed KD and Bmax values similar to those for 5-HT1B sites labeled by [3H]5-HT. Uptake of [3H]CP-93, 129 in crude rat synaptosomes was also observed, which was potently inhibited by 5-HT uptake blockers and 5-HT but not by desipramine (NE uptake blocker) or tametraline (NE and DA uptake blocker). Because of this sensitivity to 5-HT uptake inhibitors and the structural similarity of CP-93, 129 to serotonin, [3H]CP-93, 129 uptake probably occurred in 5-HT neurons. 相似文献
8.
Reduced Bmax of [3H]-imipramine binding to platelets of depressed patients free of previous medication with 5HT uptake inhibitors 总被引:1,自引:0,他引:1
Marie-France Poirier Chawki Benkelfat Henri Loo Daniel Sechter Edouard Zarifian Anne-Marie Galzin Salomon Z. Langer 《Psychopharmacology》1986,89(4):456-461
The high-affinity binding sites for [3H]-imipramine (IMI) present in human platelets are associated with the neuronal uptake system for 5HT. It was recently demonstrated
that previous antidepressant therapy with drugs which inhibit 5HT uptake could down-regulate [3H]-IMI binding and that this effect could persist up to 1 month after the end of treatment. We therefore re-examined the reported
differences inB
max of [3H]-IMI binding in platelets between control and depressed untreated patients, to evaluate the residual influence of previous
antidepressant medication. The saturation characteristics of [3H]-IMI binding were compared in platelets from 17 depressed patients care-fully selected according to previous antidepressant
therapy and washout period, who were closely matched, for age and sex, with a group of control healthy volunteers. The results
reveal a significant decrease by 47% in theB
max of [3H]-IMI binding in platelets of untreated depressed patients when compared with controls. There was no significant modification
ofK
d values for platelet [3H]-IMI binding between the depressed and the control groups. Our results support the view that platelet [3H]-IMI binding is a useful tool as a biological marker in depression. 相似文献
9.
Paola Rocca Anne-Marie Galzin Salomon Z. Langer 《Naunyn-Schmiedeberg's archives of pharmacology》1989,340(1):41-44
Summary [3H]-Paroxetine binding to rabbit blood platelet membranes from samples obtained under light and dark conditions was examined. Animals were kept on a 14 h light (L) — 10 h dark (D) schedule and blood samples were collected at L + 7 and D + 5 h. Significant differences were found for B
max values of [3H]-paroxetine binding, with low B
max values during the light period and high B
max values during the dark period. The K
d values were not significantly different. These results confirm previous observations on light-dark differences of [3H]-imipramine binding in rabbit blood platelets suggesting the existence of a circadian rhythm for the 5-HT transporter complex.Send offprint requests to S. Z. Langer at the above address 相似文献
10.
Drug inhibition against [3H]paroxetine binding to rat cortex and human putamen was investigated in saturation experiments. The addition of 5-HT, imipramine, citalopram and clomipramine all produced changes in apparent binding affinity (Kd) without changes in the number of binding sites (Bmax). These data suggest that there is no heterogeneity of specific [3H]paroxetine binding, supporting a single site model of the 5-HT uptake site and antidepressant binding site. 相似文献
11.
Mario Marchi Adriano Augliera Agnese Codignola Gianluigi Lunardi Ernesto Fedele Giovanni Fontana Maurizio Raiteri 《Naunyn-Schmiedeberg's archives of pharmacology》1991,344(3):275-280
Summary Dendrosomes prepared from substantia nigra are able to take up and release [3H]dopamine in a Ca2+-dependent manner. The Vmax values of [3H]dopamine uptake in substantia nigra dendrosomes was about 5 times lower than that in caudate putamen synaptosomes. The pattern of the K+-dependency of the [3H]dopamine release in substantia nigra dendrosomes was significantly different from that found in caudate putamen synaptosomes. The release of [3H]dopamine evoked by 15 mmol/l KCl from superfused dendrosomes was increased in a concentration-dependent manner by acetylcholine. The maximal potentiation produced by acetylcholine was about 40%. The potentiation of [3H]dopamine release by 10 µmol/l acetylcholine was insensitive to mecamylamine but antagonized by atropine and by pirenzepine. The effects of acetylcholine on the release of [3H]acetylcholine from substantia nigra nerve endings was also studied. Exogenous acetylcholine added to the superfusion medium decreased in a concentration-dependent manner the release of acetylcholine. This effect was not antagonized by mecamylamine or pirenzepine but fully antagonized by atropine. The data suggest the existence, in the substantia nigra of the rat, of two distinct muscarinic receptor subtypes regulating respectively dopamine release from dopamine dendrites and acetylcholine release from cholinergic nerve terminals.Part of this work was presented at a satellite meeting of the 11th International Congress of Pharmacology: Dopamine '90 held in Como, Italy (July 1990)
Send offprint requests to M. Raiteri at the above address 相似文献
12.
Daniel Hoyer Christian Waeber Angela Karpf Hans Neijt Jose M. Palacios 《Naunyn-Schmiedeberg's archives of pharmacology》1989,340(4):396-402
Summary The binding characteristics of [3H]ICS 205-930, a 5-hydroxytryptamine 5-HT3 receptor antagonist, were investigated in membranes prepared from cat and rabbit vagus nerve (VN) and superior cervical ganglion (SCG). The autoradiographic localisation of 5-HT3 recognition sites was also assessed using [3H]ICS 205-930 in slices from cat medulla oblongata, nodose ganglion and vagus nerve.[3H]ICS 205-930 bound to a homogeneous population of high affinity recognition sites in cat VN: Bmax = 201 ± 43 fmol/mg protein, pKD = 9.26 ± 0.17 and SCG: Bmax = 291 ± 40 fmol/mg, pKD = 9.35 ± 0.80 (n = 3). Competition experiments performed in membranes from cat VN and SCG with agonists and antagonists suggested the presence of a homogeneous population of [3H]ICS 205-930 recognition sites. Competition curves were steep and monophasic and were best fitted by a 1 receptor site model. The following rank order of affinity for [3H]ICS 205-930 binding sites was observed with antagonists: SDZ 206-830 = ICS 205-930 > BRL 43694 > SDZ 206–792 > quipazine > MDL 72222 > metoclopramide > mCPP and agonists: 2-methyl-5-HT = 5-HT > phenylbiguanide. A similar profile was observed for a limited series of compounds in rabbit membranes. Drugs acting at 5-HT1, 5-HT2 and dopamine receptors (domperidone, spiperone and metergoline) showed very low affinities for [3H]ICS 205-930 recognition sites. The sites labelled with [3H]ICS 205-930 in vagus nerve and superior cervical ganglion of both species displayed the pharmacological profile of a 5-HT3 receptor. There was a significant correlation between the rank order of affinity of the tested compounds for [3H]ICS 205-930 recognition sites in cat and rabbit membranes and their rank order of affinity for 5-HT3 receptors from neuroblastoma-glioma NG 108-15 cells. Autoradiographic studies suggest that [3H]ICS 205-930 binding sites are present over and around the nodose ganglion cell somata, along certain fibers of the vagus nerve and in the terminal areas of this nerve in the medullar nucleus of the vagus.The present data demonstrate that [3H]ICS 205-930 identifies 5-HT3 receptors in preparations of cat and rabbit vagus nerve and superior cervical ganglion.Send offprint requests to D. Hoyer at the above addressThe present results have been presented in part at the Winter Meeting of the British Pharmacological Society, London, December 20–22, 1988 (Hoyer et al. 1989) 相似文献
13.
Slices of rabbit hippocampus or caudate nucleus were incubated with [3H]-5-HT (0.1 µM, 60 min) or with [3H]-DA. In hippocampal tissue, the 5-HT uptake blockers chlorimipramine, fluvoxamine, and 6-nitroquipazine (0.1, 1, 10 µM) reduced the percentage content of [3H]-5-HT in a concentration dependent manner. The degree of inhibition of [3H]-5-HT content produced by the 5-HT uptake inhibitors was not affected by the MAO inhibitors pargyline or amezinium (which by themselves enhanced [3H] loading) or the catecholamine uptake inhibitor nomifensine (which by itself did not affect [3H] loading). In caudate nucleus tissue, however, the [3H]-5-HT accumulation was reduced only at the highest concentration of the 5-HT uptake blockers (10 µM). In the additional presence of the MAO inhibitors or nomifensine (which by themselves increased or diminished, respectively, the [3H] labelling) the 5-HT uptake inhibitors became more potent in reducing the percentage [3H]-5-HT accumulation of caudate nucleus slices. These results indicate (1) that a false labelling of [3H]-5-HT into dopaminergic terminals in the caudate nucleus can be prevented by nomifensine, (2) that the 5-HT uptake blockers seem to accumulate within the dopaminergic terminals, where they may display a MAO inhibitory property. The 5-HT uptake blockers were ineffective on the percentage tritium accumulation of caudate nucleus slices incubated with [3H]-DA, regardless of the presence of pargyline or nomifensine. Tritiated DA and deaminated [3H]-metabolites were separated in the superfusate of [3H]-DA-release experiments in caudate nucleus tissue. In the presence of 6-nitroquipazine the percentage efflux of unmetabolized [3H]-DA was significantly enhanced in a concentration and time dependent manner. In comparison to 6-nitroquipazine, fluvoxamine was less potent in that respect. 6-Nitroquipazine inhibited the electrically evoked [3H]-DA and [3H]-ACh release from caudate nucleus slices in a concentration dependent manner. The effects on [3H]-DA release were abolished in the presence of pargyline. The inhibition of [3H]-ACh release was significantly diminished by the D2-receptor antagonist domperidone. In conclusion, some 5-HT-related drugs may diminish the release of ACh from caudate nucleus slices via an enhanced dopaminergic transmission due to inhibition of MAO within the dopaminergic terminals. 相似文献
14.
Tritiated sertraline, a radiolabeled form of a potent and selective inhibitor of serotonin uptake, was found to bind with high affinity to rat whole brain membranes. Characterization studies showed that [3H] sertraline binding occurred at a single site with the following parameters:K
d
0.57 nM,B
max 821 fmol/mg protein,n
h
1.06. This binding was reversible; the dissociation constant calculated from kinetic measurements (K
d
0.81 nM) agreed with that determined by saturation binding experiments. [3H] Sertraline binding in the presence of serotonin, paroxetine, fluoxetine or imipramine suggested competitive inhibition of binding (large increase inK
d
with little change inB
max). The rank order of potency of inhibition of [3H] sertraline binding was similar to that of inhibition of serotonin uptake for known uptake inhibitors and the 1-amino-4-phenyltetralin uptake blockers. A marked decrease in ex vivo [3H] sertraline binding in the brain of rats 7 days after treatment withp-chloroamphetamine was consistent with the loss of serotonin uptake sites induced by this agent. The results of our study indicated that [3H] sertraline labels serotonin uptake sites in rat brain. 相似文献
15.
I. Wessler A. Klein D. Pohan J. Maclagana K. Racké 《Naunyn-Schmiedeberg's archives of pharmacology》1991,344(4):403-411
Summary Basal and stimulated outflow of radioactive acetylcholine, phosphorylcholine and choline from rat and guinea-pig isolated tracheae were measured by reverse phase HPLC followed by liquid-scintillation-spectrometry. Tracheae were stimulated either by an electrical field (transmural stimulation) or by a local stimulation of the innervating parasympathetic nerves (preganglionic stimulation). Epithelium was removed in most experiments, as the epithelium inhibits acetylcholine release.The basal tritium efflux (1,600 dpm/3min) from rat isolated tracheae incubated with [3H]choline consisted of 56% [3H]phosphorylcholine and 38% [3H]choline. Preganglionic stimulation (15 Hz, 1,200 pulses) caused a 2-fold increase in tritium outflow that was abolished by the removal of extracellular calcium or by the addition of tetrodotoxin. The stimulated outflow of tritium induced by preganglionic nerve stimulation was caused by an exclusive release of [3H]acetylcholine, whereas the efflux of [3H]phosphorylcholine and [3H]choline remained unaffected by this stimulation mode. Transmural stimulation of the rat or guinea-pig trachea, however, caused, in addition to the release of [3H]acetylcholine, the outflow of [3H]phosphorylcholine. Hexamethonium (300 mol/l) or tubocurarine (100 mol/l) inhibited (80%) the increase in tritium outflow evoked by preganglionic stimulation, but did not affect tritium outflow evoked by transmural stimulation. Oxotremorine reduced [3H]acetylcholine release evoked by both stimulation modes, but oxotremorine was less potent with transmural stimulation. Scopolamine (0.3 mol/l) enhanced (120%) the release of [3H]acetylcholine evoked by preganglionic nerve stimulation indicating the blockade of an endogenous negative muscarinic feedback mechanism. Epithelium-dependent inhibition of [3H]acetylcholine release was evident with both preganglionic and transmural stimulation.The present experiments demonstrate the release of [3H]acetylcholine evoked from the isolated trachea by stimulation of the preganglionic trunk of the parasympathetic cholinergic nerves. Qualitative and quantitative differences were observed in comparison to transmural stimulation. Preganglionic nerve stimulation allows a selective excitation of pulmonary, parasympathetic nerve fibres, mimics the physiological excitation of intramural neurones and is not followed by the liberation of phosphorylcholine from non-neuronal cells.
Send offprint requests to I. Wessler at the above address 相似文献
16.
Dirk H. G. Versteeg Tamás Csikós Henk Spierenburg 《Naunyn-Schmiedeberg's archives of pharmacology》1991,343(6):595-602
Summary The periaqueductal gray is a brain region of considerable interest. It is innervated by monoamine-containing neurons as well as by a variety of peptidergic fiber systems, and it participates in the regulation of various functions. Virtually nothing is known about monoamine release in the periaqueductal gray and its receptor-mediated modulation. We therefore studied the release of radioactivity from periaqueductal gray slices preloaded with tritriated monoamines, using an in vitro superfusion method.The release of radioactivity from superfused periaqueductal gray slices after preloading of the tissue with [3H]noradrenaline increased upon electrical stimulation in a frequency-dependent manner. The stimulus-evoked release of radioactivity was Ca2+-dependent. Clonidine reduced and yohimbine enhanced the release. The inhibition curve for the effect of clonidine was shifted to the right in the presence of 10–6 M yohimbine. While phenylephrine, isoprenaline, SK&F 38393, quinpirole, carbachol, [Arg8]vasopressin, -MSH and ACTH-(1-24), at a concentration of 10–6 M, did not influence the electrically evoked release of radioactivity, [Leu5]enkephalin reduced it. The selective -opioid receptor agonists [d-Ala2,NMePhe4,Gly-ol5]enkephalin and [d-Arg2,Lys4]-dermorphin-(1–4)-amide reduced the release of radioactivity, whereas the selective opioid receptor agonist [d-Pen2,d-Pen5]enkephalin and the selective K opioid receptor agonist U-69593 had no effect. In the presence of naloxone, which by itself had no effect on the release of radioactivity, the effect of [d-Arg2,Lys4]dermorphin-(1–4)-amide was abolished. These results show that the release of noradrenaline from periaqueductal gray slices is via a Ca2+-dependent. exocytotic process, and that it is modulated through 2-adrenoceptors as well as via -opioid receptors. Though the overflow of radioactivity from slices preloaded with [3H]dopamine in the presence of desipramine was measurable, there are reasons to assume that we are dealing here with the release of tritiated catecholamines from a population of nerve endings consisting of noradrenergic and dopaminergic terminals.The release of radioactivity from periaqueductal gray slices preloaded with [3H]5-hydroxytryptamine upon elevation of the K+ concentration in the superfusion medium was much more pronounced than that induced by electrical stimulation. The K+-evoked release of radioactivity was almost completely abolished in the absence of Cat2+; showing that the release is via a Ca2+-dependent process. 5-Hydrotryptamine reduced the K+-evoked release of radioactivity in a concentration-dependent manner.Some of these data were presented at the XIth International Congress of Pharmacology, 1–6 July 1990, Amsterdam, The Netherlands (Eur J Pharmacol 183:408)
Send offprint requests to D. H. G. Versteeg at the above address 相似文献
17.
Michael P. Johnson Barry W. Siegel Albert A. Carr 《Naunyn-Schmiedeberg's archives of pharmacology》1996,354(2):205-209
In studies using standard radioligands, unlabeled MDL 100,907 (R-(+)--(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol) has been shown to have a high degree of selectivity for the 5-HT2A receptor. The present study was undertaken to investigate the receptor binding characteristics of [3H]MDL 100,907 in rat cortical homogenates. [3H]MDL 100,907 was found to reach equilibrium at 37°C after 15 min. Saturation experiments indicated binding to a single site with a KD of 0.56 nM, Hill slope of 1.15, and a Bmax of 512 fmol/mg protein. In parallel experiments with the standard 5-HT2A receptor radioligand, [3H]ketanserin, with prazosin added to block 1 receptors, a similar Hill slope and Bmax was noted but a two-fold higher KD was found. In competition binding studies using 0.5 nM [3H]MDL 100,907, some 19 standard ligands to various receptors including the 5HT1A, D2, 1, and receptors resulted in estimated KI values that were consistent with [3H]MDL 100,907 selectively binding to the 5-HT2A receptor. A comparison of the KI values for 17 standard 5-HT2A receptor agonists and antagonists displacing [3H]MDL 100,907 versus [3H]ketanserin resulted in a highly significant linear correlation (R2 = 0.96, P<0.001). Taken together these results suggest that [3H]MDL 100,907 is binding to the 5-HT2A receptor with a sub-nanomolar affinity without the use of secondary blocking agents. 相似文献
18.
Ketamine interacts with the noradrenaline transporter at a site partly overlapping the desipramine binding site 总被引:5,自引:0,他引:5
Koji Hara N. Yanagihara Kouichiro Minami Susumu Ueno Yumiko Toyohira Takeyoshi Sata Masaru Kawamura Michael Brüss Heinz Bönisch Akio Shigematsu Futoshi Izumi 《Naunyn-Schmiedeberg's archives of pharmacology》1998,358(3):328-333
Effects of the intravenous anaesthetic ketamine on the desipramine-sensitive noradrenaline transporter (NAT) were examined
in cultured bovine adrenal medullary cells and in transfected Xenopus laevis oocytes expressing the bovine NAT (bNAT). Incubation (1–3 h) of adrenal medullary cells with ketamine (10–300 μM) caused
an increase in appearance of catecholamines in culture medium. Ketamine (10–1000 μM) inhibited desipramine-sensitive uptake
of [3H] noradrenaline (NA) (IC50=97 μM). Saturation analysis showed that ketamine reduced V
max of [3H]NA uptake without changing K
m, indicating a non-competitive inhibition. Other inhibitors of NAT, namely cocaine and desipramine, showed a competitive inhibition
of [3H]NA uptake while a derivative of ketamine, phencyclidine, showed a mixed type of inhibition. Ketamine (10–1000 μM) also inhibited
the specific binding of [3H]desipramine to plasma membranes isolated from bovine adrenal medulla. Scatchard analysis of [3H]desipramine binding revealed that ketamine increased K
d without altering B
max, indicating a competitive inhibition. In transfected Xenopus oocytes expressing the bNAT, ketamine attenuated [3H]NA uptake with a kinetic characteristic similar to that of cultured adrenal medullary cells. These findings are compatible
with the idea that ketamine non-competitively inhibits the transport of NA by interacting with a site which partly overlaps
the desipramine binding site on the NAT.
Received: 18 December 1997 / Accepted: 17 June 1998 相似文献
19.
The effect of the psychomotor stimulant, 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”), upon integrated cerebral function
was measured in rats using the quantitative [14C]deoxyglucose autoradiographic technique. Animals were injected with MDMA (20 mg/kg sc) twice daily for 4 days. Fourteen
days after the final administration, [3H]-paroxetine binding to 5HT uptake sites was reduced by 89% in membranes prepared from tissue samples of frontal cortex.
In the same rats [3H]-paroxetine binding autoradiography revealed heterogeneity in the regional distribution of 5-HT uptake site depletion within
neocortex (0–92%) and hippocampus (30–95%). Despite these profound reductions in 5-HT uptake sites no significant alterations
were found in glucose utilisation in any area of neocortex examined. However, significant increases in glucose use were found
in subregions of the hippocampus, most notably within the pyramidal cell layer of CA2 and CA3 (25–35%). This study provides
direct evidence that the loss of 5-HT innervation caused by exposure to MDMA results in lasting functional changes in hippocampus. 相似文献
20.
Binding of some antidepressants to the 5-hydroxytryptamine transporter in brain and platelets 总被引:1,自引:1,他引:0
Antidepressant agents with properties to inhibit 5-hydroxytryptamine (5-HT, serotonin) uptake in brain tissue and platelets bind with high affinities to neuronal and platelet membranes. [3H]Imipramine, [3H]paroxetine and [3H]citalopram label specific binding sites related to the 5-HT transporter. [3H]Paroxetine and [3H]citalopram appear to be better ligands than [3H]imipramine. The former label a homogenous population of binding sites, whereas the displaceable binding of [3H]imipramine is heterogenous. Recent observations in several laboratories, which have taken the heterogeneity of [3H]imipramine binding into account, indicate that the binding of antidepressants to the 5-HT transporter probably occurs to the same site that binds 5-HT for transport and not to a separate site as previously suggested. Additional bonds to subsites in close vicinity to the 5-HT recognition site may contribute to the binding. No convincing evidence has been presented of the existence of an endogenous ligand other than 5-HT itself that binds to the [3H]imipramine binding site. Recent studies also suggest that repeated treatment of rats with antidepressant agents does not produce any alterations of the binding of [3H]imipramine or [3H]paroxetine to membranes of cerebral cortex. It is also doubtful whether the density of the 5-HT uptake site in platelets measured with these ligands is decreased in affective disorders as first reported. 相似文献