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1.
Serotonin (5-HT), substance P (SP), neurokinin A (NKA), and thyrotropin-releasing hormone (TRH) coexist in the nerve terminals of the intermediolateral cell column (IML) of the thoracic spinal cord. The Ca2+-dependent release of 5-HT from the microdissected intermediate area (including the IML) of the rat thoracic spinal cord, and the 5-HT1B autoreceptor regulator of 5-HT release, were previously demonstrated. In this paper, the effects of SP, NKA, TRH, and/or their analogs on the release of [3H]5-HT from the intermediate area were investigated using an in vitro superfusion system. Both SP (the endogenous ligand for neurokinin-1 (NK1) receptor) and an NK1, agonist (GR 73632) significantly increased the basal release of [33H]5-HT. SP and GR 73632 did not change the K+-stimulated release of [3H]5-HT. The effect of the NK1 agonist on the basal release of [3H]5-HT was dose-dependent, was reduced by an NK1 antagonist (GR 82334), and was not dependent on extracellular Ca2+. Neither NKA, an NK2, agonist (GR 64349), nor a TRH analog (MK-771) altered the basal or stimulated release of [3H]5-HT. These data suggest that basal release of 5-HT from the intermediate area of the rat thoracic spinal cord is regulated by SP (acting through an NK1 receptor), but not by NKA or TRH. These results provide evidence for the role of SP as a modulator of serotoninergic neurons in the intermediate area of the thoracic spinal cord, and may help to clarify the role of coexisting neurochemicals in the spinal regulation of the sympathetic nervous system. © 1995 Wiley-Liss, Inc.
  • 1 This article is a US Government work and, as such, is in the public domain in the United States of America.
  •   相似文献   

    2.
    The 5-HT3 agonist 2-methyl-5-HT had previously been shown to enhance the electrically evoked release of [3H]5-HT from preloaded slices of the guinea pig brain. In the present study, 2-methyl-5-HT (1 μM) was also found to increase the K+ evoked release of [3H]5-HT from preloaded slices of the guinea pig hypothalamus and this effect was blocked by the selective 5-HT3 antagonist ondansetron. In the presence of tetrodotoxin, the enhancement of the K+-evoked release of [3H]5-HT by 2-methyl-5-HT in hypothalamus slices was blocked, thus suggesting that the 5-HT3 receptors mediating this effect are not located directly on 5-HT terminals. In agreement with this, 2-methyl5-HT did not alter the K+-evoked release of [3H]5-HT in a synaptosomal preparation of the same brain structure, even at a concentration 10-fold greater than that used in the slices. Taken together, these data indicate that these facilitatory 5-HT3 receptors are not located on 5-HT terminals in the guinea pig hypothalamus and therefore are not autoreceptors. © 1993 Wiley-Liss, Inc.  相似文献   

    3.
    Substance P (SP) nerve terminals innervate the intermediolateral cell column (IML) of the thoracic spinal cord, where SP coexists with serotonin (5-HT), neurokinin A (NKA) and thyrotropin-releasing hormone (TRH). Neither the depolarization-induced release of SP nor the presence of other neurochemicals in the regulation of SP release has been directly studied in this system. In the present study, basal and K+-stimulated release of SP from the microdissected intermediate area (including the IML, intercalated nucleus and central autonomic nucleus) of the rat thoracic spinal cord, and the regulation of SP release by presynaptic autoreceptors and by coexisting neurochemicals (5-HT, NKA and TRH) were studied using an in vitro superfusion system. Potassium evoked a concentration- and extracellular Ca2+-dependent release of SP. In rats pretreated with the serotoninergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), both SP content and the absolute amount of SP released were decreased. However, the fraction of the remaining tissue content of SP released by K+ depolarization was not changed subsequent to 5,7-DHT treatment. Moreover, 5-HT, 5-HT1B agonists (CGS-12066B and RU 24969) and a 5-HT3 agonist (2-methyl-5-HT) did not alter the K+-evoked release of SP. These data demonstrate that SP is released from the intermediate area of the rat thoracic spinal cord and some of the SP released comes from serotoninergic nerve terminals. Although 5-HT coexists with SP in the IML, neither endogenous 5-HT nor 5-HT receptor ligands appear to regulate the release of SP. Other colocalized neuropeptides (NKA and TRH) are not involved in the regulation of SP release because neither NKA, a NK2 agonist (GR 64349) nor a TRH analog (MK-771) changed the K+-evoked release of SP. A neurokinin-1 (NK1) antagonist (GR 82334) dose-dependently (10-9-10-7 M) increased the K+ stimulated release of SP. These data suggest the presence of presynaptic inhibitory NK1 autoreceptors. Whereas, NK1 agonists, [GR 73632 (10-9-10-6 M) and [Sar9, Met (O2)1]] SP (10-8-10-6 M)], increased the basal and K+-stimulated release of SP, the excitatory effects of GR 73632 were not blocked by the NK1 antagonist. Moreover, GR 73632 increased the efflus of SP to a greater extent in the absence of peptidase inhibitors. Thus, the effect of NK1 agonists on the release of SP may be related to an inhibition of peptide degradation rather than activation of NK1 autoreceptors. © 1996 Wiley-Liss, Inc.
  • 1 This article is a US Government work and, as such, is in the public domain in the United States of America.
  •   相似文献   

    4.
    《Brain research》1997,757(1):205
    The role of 5-hydroxytryptamine (5-HT) receptor subtypes in acetylcholine (ACh) release induced by dopamine or neurokinin receptor stimulation was studied in rat striatal slices. The dopamine D1 receptor agonist SKF 38393 potentiated in a tetrodotoxin-sensitive manner the K+-evoked [3H]ACh release while SCH 23390, a dopamine D1 receptor antagonist, had no effect. [3H]ACh release was decreased by the dopamine D2 receptor agonist LY 171555 (quinpirole) and slightly potentiated by the dopamine D2 receptor antagonist haloperidol. The selective neurokinin NK1 receptor agonist [Sar9, met(O2)11]SP also potentiated K+-evoked release of [3H]ACh. GR 82334, a NK1 receptor antagonist, blocked not only the effect of [Sar9, met(O2)11]SP but also the release of ACh induced by the D1 receptor agonist SKF 38393. Among the 5-HT agents studied, only the 5-HT2A receptor antagonists ketanserin and ritanserin were able to reduce the ACh release induced by dopamine D1 receptor stimulation. Mesulergine, a more selective 5-HT2C antagonist, showed an intrinsic releasing effect but did not affect K+-evoked ACh release induced by SKF 38393. Methysergide and methiothepin, mixed 5-HT1/2 antagonists, as well as ondansetron, a 5-HT3 receptor antagonist, showed an intrinsic effect on ACh release, their effects being additive to that of SKF 38393. 5-HT2 receptor agonists were ineffective. However, the 5-HT2 agonist DOI was able to prevent the antagonism by ketanserin of the increased [3H]ACh efflux elicited by SKF 38393, suggesting a permissive role of 5-HT2A receptors. None of the above indicated 5-HT agents was able to reduce the ACh release induced by the selective NK1 agonist. The results suggest that 5-HT2 receptors, probably of the 5-HT2A subtype, modulate the release of ACh observed in slices from the rat striatum after stimulation of dopamine D1 receptors. It seems that this serotonergic control is exerted on the interposed collaterals of substance P-containing neurons which promote ACh efflux through activation of NK1 receptors located on cholinergic interneurons.  相似文献   

    5.
    [3H]5-Hydroxytryptamine ([3H]5-HT) and [3H]mesulergine were used to label 5-HT1C receptors expressed in NIH 3T3 mouse fibroblast cells. Using a rapid filtration assay, saturation analysis of the [3H]5-HT radioligand data indicate that the binding is biphasic. Based on computerized analysis of the data, a 2-site model of radioligand binding is significantly more consistent with the data than a one-site model (P < 0.01). The KD values of [3H]5-HT for the 2 populations are0.5±0.1nM and31±15nM, while the Bmax values are400±90pmol/g protein and 3,000±600 pmol/g protein, respectively. A biphasic binding pattern is also observed with [3H]5-HT using a centrifugation assay (KD1 = 0.6±0.06nM, KD2 = 60±10nM;Bmax1 = 740±90pmol/g, Bmax2 = 4,000±700pmol/g). By contrast, saturation analysis of [3H]mesulergine binding is monophasic (KD = 4.7±0.7nM) with a Bmax value (6,800±1,000pmol/g protein) that is significantly greater than that obtained using [3H]5-HT (P < 0.01). Drug competition studies confirm that both [3H]5-HT and [3H]mesulergine label at least 2 subpopulations of expressed 5-HT1C receptors in NIH 3T3 cells. 10−4 M GTP eliminates the high affinity [3H]5-HT-labeled binding sites with minimal effect on the low affinity [3H]5-HT-labeled sites and no effect on [3H]mesulergine-labeled sites. These data demonstrate that at least 2 distinct subpopulations of 5-HT1C receptors in NIH 3T3 cells can be differentiated using radioligand binding techniques.  相似文献   

    6.
    Microiontophoretic applications of 5-HT and of the 5-HT3 agonist 2-methyl-5-HT produced a current-dependent suppression of firing activity of both hippocampal (CA1 and CA3) and cortical neurons in anesthetized rats. Concomitant microiontophoretic applications of the 5-HT3 antagonists BRL 46470A and S-zacopride, as well as their intravenous injection, did not antagonize the inhibitory effect of 5-HT and 2-methyl-5-HT. In contrast, the 5-HT1A antagonist BMY 7378, applied by microiontophoresis or administered intravenously, significantly reduced the inhibitory action of 5-HT and 2-methyl-5-HT. The firing activity of dorsal raphe 5-HT neurons was also reduced by 5-HT, 2-methyl-5-HT and the 5-HT1A agonist 8-OH-DPAT applied by microiontophoresis. While BRL 46470A (0.1 and 1 mg/kg, i.v.) did not antagonize the inhibitory effect of the three 5-HT agonists on 5-HT neuronal firing activity, only that of 8-OH-DPAT was attenuated by the 5-HT1A antagonist (+) WAY 100135. R-zacopride significantly reduced the duration of suppression of firing activity of CA3 pyramidal neurons induced by the electrical stimulation of the ascending 5-HT pathway, and this reducing effect was prevented by the three 5-HT3/5-HT4 antagonists renzapride, S-zacopride and tropisetron, but not by BRL 46470A. Finally, in in vitro superfusion experiments, both BRL 46470A and S-zacopride antagonized the enhancing action of 2-methyld-HT on the electrically-evoked release of [3H]-5-HT in both rat frontal cortex and hippocampus slices. These findings suggest that, in vivo, the suppressant effect of 2-methyl-5-HT on the firing activity of dorsal hippocampus pyramidal, somatosensory cortical, and dorsal raphe 5-HT neurons is not mediated by 5-HT3 receptors, but rather by 5-HT1A receptors. The attenuating effect of R-zacopride on the effectiveness of the stimulation of the ascending 5-HT pathway is not mediated by 5-HT3 receptors. In contrast, in vitro, the enhancing action of 2-methyl-5-HT on the electrically-evoked release of [3H]5-HT in both frontal cortex and hippocampus slices is mediated by 5-HT3 receptors. © 1995 Wiley-Liss, Inc.  相似文献   

    7.
    5-Hydroxytryptamine (5-HT, serotonin), synthesized in midbrain raphe nuclei and released in various hypothalamic sites, decreases food intake but the specific 5-HT receptor subtypes involved are controversial. Here, we have studied changes in the regional density of binding to 5-HT receptors and transporters and the levels of tryptophan hydroxylase, in rats with obesity induced by feeding a palatable high-energy diet for 7 weeks. We mapped binding at 5-HT receptor subtypes and transporters using quantitative autoradiography and determined tryptophan hydroxylase protein levels by Western blotting. In diet-induced obese (DiO) rats, specific binding to 5-HT1A receptors ([3H]8-OH-DPAT) was significantly increased in the dorsal and median raphe by 90% (P<0.01) and 132% (P<0.05), respectively, compared with chow-fed controls. 5-HT1B receptor binding sites ([125I]cyanopindolol) were significantly increased in the hypothalamic arcuate nucleus (ARC) of DiO rats (58%; P<0.05), as were 5-HT2A receptor binding sites ([3H]ketanserin) in both the ARC (44%; P<0.05) and lateral hypothalamic area (LHA) (121%; P<0.05). However, binding to 5-HT2C receptors ([3H]mesulgergine) in DiO rats was not significantly different from that in controls in any hypothalamic region. Binding to 5-HT transporters ([3H]paroxetine) was significantly increased (P<0.05) in both dorsal and median raphe, paraventricular nuclei (PVN), ventromedial nuclei (VMH), anterior hypothalamic area (AHA) and LHA of DiO rats, by 47%–165%. Tryptophan hydroxylase protein levels in the raphe nuclei were not significantly different between controls and DiO rats. In conclusion, we have demonstrated regionally specific changes in binding to certain 5-HT receptor subtypes in obesity induced by voluntary overeating of a palatable diet. Overall, these changes are consistent with reduced 5-HT release and decreased activity of the 5-HT neurons. Reduction in the hypophagic action of 5-HT, possibly acting at 5-HT1A, 5-HT1B and 5-HT2A receptors, may contribute to increased appetite in rats presented with highly palatable diet.  相似文献   

    8.
    Slices from rat midbrain containing the raphe nuclei and from hippocampus were prepared, loaded with [3H]5-HT and superfused and the resting and the electrically stimulated [3H]5-HT release was measured. The 5-HT3 receptor agonist 2-methyl-5-HT (1 to 10 μmol/l) increased the resting tritium outflow in superfused raphe nuclei slices, EC50 5.3 μmol/l. The 2-methyl-5-HT-induced increase of tritium outflow was an external Ca2+-independent process and was not altered by reserpine pretreatment but it was reversed by addition of the 5-HT uptake inhibitor fluoxetine (1 μmol/l). The 5-HT3 receptor antagonists ondansetron and GYKI-46 903 (1 μmol/l) did not antagonize the stimulatory effect of 2-methyl-5-HT on resting tritium outflow. 2-Methyl-5-HT in lower concentration increased the electrically induced tritium overflow from raphe nuclei slices (EC50 0.56 μmol/l) and also from hippocampal slices preloaded with [3H]5-HT. These effects were reversed by 1 μmol/l of ondansetron and GYKI-46903. The 5-HT3 receptor antagonists (1 μmol/l) were without effects on depolarization-evoked [3H]5-HT release at 2 Hz stimulation, when 10 Hz stimulation was used, ondansetron and GYKI-46 903 reduced the tritium overflow from raphe nuclei slices. These data indicate that 5-HT3 receptors positively alter depolarization-induced somatodendritic 5-HT release in the raphe nuclei. They also show that 2-methyl-5-HT is able to evoke 5-HT release not only from vesicles but also from cytoplasmic stores via a transporter-dependent exchange process.  相似文献   

    9.
    The aim of the present study was to examine the role of 5-HT3 receptors in spontaneous and K+-evoked acetylcholine (ACh) release from rat entorhinal cortex and striatal slices. The 5-HT3 receptor antagonists ondansetron and granisetron (0.01–10 μM) produced a concentration-dependent increase in both spontaneous and K+-evoked [3H]ACh release in the two brain regions studied. The release of ACh was Ca2+-dependent and tetrodotoxin-sensitive. 5-HT3 receptor agonists, such as 2-methyl-5-HT and 1-phenylbiguanide, at concentrations up to 1 μM, did not show any intrinsic effect on [3H]ACh release in both rat brain regions. However, 2-methyl-5-HT, 1 μM, fully blocked the ondansetron-induced enhancement in both basal and K+-evoked ACh release, suggesting that 5-HT3 through 5-HT3 receptor activation, tonically inhibits ACh release. The possible implication of interposed inhibitory systems in ACh release after 5-HT3 receptor blockade was subsequently analyzed. While the effect of ondansetron was not modified by haloperidol or naloxone, the GABAA receptor antagonist bicuculline produced a marked potentiation of ACh release in the entorhinal cortex but not in the striatum. The results suggest that in this cortical area 5-HT activates 5-HT3 receptors located on GABAergic neurons which in turn inhibit cholinergic function.  相似文献   

    10.
    The effect of verapamil on resting and depolarization-induced monoamine release was investigated in rat hippocampal synaptosomes prelabeled with [3H]-5-hydroxytryptamine (HT) or [3H]-norepinephrine (NE) and rat striatal synaptosomes prelabeled with [3H]-dopamine (DA). Verapamil (50 μM) completely abolishes high K+-induced [3H]-NE release, but paradoxically facilitates high K+-induced [3H]-5-HT and [3H]-DA release. All these high K+-evoked responses were Ca2+ dependent. Verapamil does not modify [3H]-NE baseline release, but increases dose dependently [3H]-5-HT and [3H]-DA baseline release. Verapamil (10 μM, for 5 min) increases endogenous DA release (70%) and endogenous 5-HT release (40%) independently on the presence of external Ca2+. The total amount of these monoamines (released plus retained by the preparation) and their metabolites (DOPAC and 5-HIAA) was similar in control and verapamil-treated synaptosomes. Verapamil displaces [3H]-spiroperidol specific binding (Ki of 2.4 × 10?6M) and [3H]-SCH-23390 specific binding (Ki of 9 × 10?6M) from striatal synaptosomal membranes, and [3H]-5-HT specific binding (Ki of 3 × 10?5M) from hippocampal synaptosomal membranes. It is concluded that in addition to the Ca2+ antagonistic properties of verapamil on the Ca2+-dependent, depolarization-induced release of some neurotransmitters [gamma aminobutyric acid (GABA and NE)], another mechanism probably mediated by presynaptic receptors underlies the effects of verapamil on DA and 5-HT release from discrete brain regions. © 1995 Wiley-Liss, Inc.  相似文献   

    11.
    Summary Serotonin (5-hydroxytryptamine, 5-HT) synthesis was determined in vivo by measuring the accumulation of 5-hydroxytryptophan (5-HTP) in rat frontal cortex after inhibition of aromatic amino acid decarboxylase by administration of m-hydroxybenzylhydrazine (NSD 1015) (100 mg/kg, i.p.). The selective 5-HT reuptake inhibitor, citalopram, the 5-HT1a agonists, (±)8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), ipsapirone, gepirone and the 5-HT1a/b agonist, 7-trifluoromethyl-4(4-methyl-1-piperazinylpyrolo[1,2-a]-quinoxaline (CGS 12066B), the 5-HT1a/b ligands and -adrenoceptor antagonists, (±)pindolol and (±)alprenolol, and the non-selective 5-HT ligands, m-chlorophenylpiperazine (mCPP) and metergoline, all inhibited the synthesis of 5-HT. The 5-HT1a /5-HT2 antagonist, spiperone, alone, had no effect on basal 5-HT synthesis, however it attenuated the effect of 8-OH-DPAT by 56% and CGS 12066B by 39% but only barely that of citalopram by 17%. The selective 5-HT1a antagonist, WAY 100635, which did not modify by itself 5-HT synthesis, had no effect on citalopram-induced reduction of 5-HT synthesis. Neither the 5-HT2 agonist, (±)1-(2,5-dimethoxy-4-indophenyl)-2-aminopropane (DOI) nor the 5-HT2 antagonist, ritanserin, had any effect on the synthesis of 5-HT. In addition, ritanserin did not modify the inhibitory effect of citalopram. Methiothepin was the only compound to increase 5-HT synthesis. These results suggest that the effect of citalopram on the synthesis of 5-HT is not mediated by 5-HT1a or 5-HT2 receptors and that other receptors may be involved.  相似文献   

    12.
    The effect of ionophoretically applied serotonin (5-HT) was tested on cutaneous sensory responses of multireceptive dorsal horn neurones in the anaesthetized rat. Three types of 5-HT action were discerned: selective inhibition of nociceptive responses (10/18 cells), non-selective inhibition of responses to both noxious and innocous stimuli as well as to excitatory amino acids (4/18 cells) and non-selective excitation of evoked responses (1/18 cells). A few cells (3/18) were unaffected by 5-HT. The use of agonists, shown to discriminate between subtypes of 5-HT1 receptor revealed that a 5-HT1A receptor agonist mimicked the non-selective effects of 5-HT, whereas a 5-HT1B receptor agonist mimicked the selective antinociptive effects of 5-HT. A 5-HT2 receptor agonist, in contrast, was without effect. Both the selective and the non-selective effects were reversed by a 5-HT1 receptor antagonist, but not a 5-HT2 antagonist.  相似文献   

    13.
    Fimbria-fornix lesions disrupt important parts of serotonergic and noradrenergic hippocampal afferents and elicit sprouting of sympathetic fibers from the superior cervical ganglion. Since 5-hydroxytryptamine (5-HT) release in the hippocampus is modulated by 5-HT1B auto- and α2-heteroreceptors, we investigated whether such lesions may alter these presynaptic mechanisms. Hippocampal slices of sham-operated (SHAM) and fimbria-fornix–lesioned (LES) rats (14 months after surgery) were preincubated with [3H]5-HT, superfused continuously, and stimulated electrically using two stimulation conditions: either (a) 360 pulses 3 Hz, or (b) 20 pulses 100 Hz (2 ms, 28 mA, 4 V/chamber). The amount of [3H]5-HT taken up by slices from LES rats was significantly reduced, whereas the evoked 5-HT release (in percent of tissue-3H) was unchanged compared to that of SHAM rats. The 5-HT1B agonist CP 93,129 or the α2-agonist UK 14,304 reduced the evoked 5-HT release more potently in slices from LES rats, but only using stimulation condition (a), which permits inhibition by endogenously released transmitters. In LES rats, the facilitatory effect of the 5-HT antagonist metitepine was weaker, whereas that of the α2-antagonist idazoxane was more pronounced than in SHAM rats. In LES rats, hippocampal 5-HT content was reduced to about 45% of SHAM levels, whereas that of noradrenaline was increased by about 30% (high-performance liquid chromatography). We conclude: (1) despite LES-induced changes in tissue levels of endogenous ligands, there is no down- or upregulation of 5-HT1B-autoreceptors or α2-heteroreceptors on serotonergic neurons in the denervated rat hippocampus. (2) The reduced endogenous autoinhibition (by 5-HT) seems to be compensated for by an increased heteroinhibition (by noradrenaline).  相似文献   

    14.
    The outflow of [3H]5-hydroxytryptamine ([3H]5-HT) from electrically stimulated rat cortical slices was measured to ascertain the modulatory role of endogenous cholecystokinin (CCK) on the amine outflow and to test the hypothesis that different anxiolytic compounds inhibit 5-HT secretion. The [3H]5-HT outflow evoked at 10 Hz was increased up to +30% by CCK4 300–1000 nM, the effect being prevented by the CCKB receptor antagonist GV 150013, 3 nM. The limited sensitivity to CCK4 seemed to depend on 5-HT auto-receptor feedback because pre-treatment with 100 nM methiothepin enhanced the [3H]5-HT outflow and lowered the CCK4 threshold concentration from 300 to 30 nM. In addition, pre-treatment with 1 μM bacitracin to inhibit CCK metabolism increased [3H]5-HT efflux. This effect was concentration-dependently counteracted by GV150013 suggesting the presence of an endogenous CCK positive modulation. GV150013 30 nM, the 5-HT1A partial agonist buspirone 300 nM and the GABAA receptor modulator diazepam 10 nM, known to have anxiolytic properties, all significantly reduced the [3H] amine outflow from cortical slices by about 20%. This inhibition depended on their interaction with their respective receptors, which seemed to restrain the activity of functionally interconnected glutamatergic interneurones. In fact, APV (50 μM) and NBQX (10 μM) prevented the effect of the anxiolytic compounds. Thus, anxiolytic drugs with different receptor targets can reduce 5-HT outflow by dampening the glutamatergic signal, and in turn, the secretory process of the serotonergic nerve ending.  相似文献   

    15.
    We have used intracellular recording techniques to examine the effects of 5-hydroxytryptamine (5-HT, serotonin) on 5-HT-containing neurones of the guinea pig dorsal raphe nucleus in vitro. Bath-applied 5-HT (30–300 μM) had two opposing effects on the membrane excitability of these cells, reflecting the activation of distinct 5-HT receptor subtypes. As demonstrated previously in the rat, 5-HT evoked a hyperpolarization and inhibition of 5-HT neurones, which appeared to involve the activation of an inwardly rectifying K+ conductance. This hyperpolarizing response was blocked by the 5-HT1A receptor-selective antagonist WAY-100635 (30–100 nM). In the presence of WAY-100635, 5-HT induced a previously unreported depolarizing, excitatory response of these cells, which was often associated with an increase in the apparent input resistance of the neurone, likely due to the suppression of a K+ conductance. Like the hyperpolarizing response to 5-HT, this depolarization could be recorded in the presence of the Na+ channel blocker tetrodotoxin. In addition, the response was not significantly attenuated by the α1-adrenoceptor antagonist prazosin (500 nM), indicating that it is not due to the release of noradrenaline, or to the direct activation of α1-adrenoceptors by 5-HT. The 5-HT3 receptor antagonist granisetron (1 μM) and the 5-HT4 receptor antagonist SB 204070 (100 nM) failed to reduce the depolarizing response to 5-HT; however, ketanserin (100 nM), mesulergine (100 nM) and lysergic acid diethylamide (1 μM) significantly reduced or abolished the depolarization, indicating that this effect of 5-HT is mediated by 5-HT2 receptors.  相似文献   

    16.
    Adult Long-Evans female rats sustained electrolytic fimbria-fornix lesions and, two weeks later, received intrahippocampal suspension grafts of fetal septal tissue. Sham-operated and lesion-only rats served as controls. Between 6.5 and 8 months after grafting, both the [3H]choline accumulation and the electrically evoked [3H]acetylcholine ([3H]ACh) release were assessed in hippocampal slices. The release of [3H]ACh was measured in presence of atropine (muscarinic antagonist, 1 μM), physostigmine (acetylcholinesterase inhibitor, 0.1 μM), oxotremorine (muscarinic agonist, 0.01 μM–10 μM), mecamylamine (nicotinic antagonist, 10 μM), methiothepin (mixed 5-HT1/5-HT2 antagonist, 10 μM), 8-OH-DPAT (5-HT1A agonist, 1 μM), 2-methyl-serotonin (5-HT3 agonist, 1 μM) and CP 93129 (5-HT1B agonist, 0.1 μM–100 μM), or without any drug application as a control. In lesion-only rats, the specific accumulation of [3H]choline was reduced to 46% of normal and the release of [3H]ACh to 32% (nCi) and 43% (% of tissue tritium content). In the grafted rats, these parameters were significantly increased to 63%, 98% and 116% of control, respectively. Physostigmine reduced the evoked [3H]ACh release and was significantly more effective in grafted (−70%) than in sham-operated (−56%) or lesion-only (−54%) rats. When physostigmine was superfused throughout, mecamylamine had no effect. Conversely, atropine induced a significant increase of [3H]ACh release in all groups, but this increase was significantly larger in sham-operated rats (+209%) than in the other groups (lesioned: +80%; grafted: +117%). Oxotremorine dose-dependently decreased the ([3H]ACh) release, but in lesion-only rats, this effect was significantly lower than in sham-operated rats. Whatever group was considered, 8-OH-DPAT, methiothepin and 2-methyl-serotonin failed to induce any significant effect on [3H]ACh release. In contrast, CP 93129 dose-dependently decreased [3H]ACh release. This effect was significantly weaker in grafted rats than in the rats of the two other groups. Our data confirm that cholinergic terminals in the intact hippocampus possess inhibitory muscarinic autoreceptors and serotonin heteroreceptors of the 5-HT1B subtype. They also show that both types of receptors are still operative in the cholinergic terminals which survived the lesions and in the grafted cholinergic neurons. However, the muscarinic receptors in both lesioned and grafted rats, as well as the 5-HT1B receptors in grafted rats show a sensitivity which seems to be downregulated in comparison to that found in sham-operated rats. In the grafted rats, both types of downregulations might contribute to (or reflect) an increased cholinergic function that results from a reduction of the inhibitory tonus which ACh and serotonin exert at the level of the cholinergic terminal.  相似文献   

    17.
    The distribution of the binding sites of a new, potent agonist of serotonin (5-HT), 8-OH-N,N-dipropoyl-2-aminotetralin (PAT), was studied in the rat brain with the quantitative autoradiographic technique utilizing tritium-sensitive LKB film. The localization of [3H]PAT binding sites was very similar to that of [3H]5-HT binding sites, except in some discrete regions (choroid plexus, striatum, area preoptica lateralis, subiculum, and substantia nigra), which exhibited very low levels of labeling with [3H]PAT and high levels with [3H]5-HT. These results indicate that 5-HT1 receptors are heterogeneous, and that [3H]PAT recognizes only a 5-HT5 subclass (called 5-HT1A).  相似文献   

    18.
    In human cortex and hippocampus area, [3H]5-HT (5 nM) labels 5-HT1A, 5-HT1D and 5-HT1E sites. After masking 5-HT1A receptors by 0.1 μM 8-OH-DPAT, the binding displaced by 0.1 μM 5-CT presumably represented 5-HT1D sites and the remaining binding 5-HT1E sites. In frontal cortex, 5-HT1A receptors represented the main binding in layers II and VI and a lower fraction on other layers. 5-HT1D and 5-HT1E sites, were more homogeneously distributed in layers II to VI (21–34% of specific [3H]5-HT binding). 5-HT1E sites were of similar affinities (KD close to 6–8 nM) in the cortical layers II to VI. In CA1 field of hippocampus, (pyramidal layer, stratum radiatum, molecular layer), CA2 and dentate gyrus, 5-HT1A receptors represented the major fraction, 5-HT1D sites a significant fraction and 5-HT1E a minor fraction of the specific [3H]5-HT binding. In CA3–CA4 fields, 5-HT1A receptors were less densely present, 5-HT1D sites were predominant and 5-HT1E sites represented a significant fraction (27%). The highest densities of 5-HT1E sites have been measured in subiculum, where 5-HT1A, 5-HT1D, and 5-HT1E binding sites were equally represented and in entorhinal cortex where 5-HT1E sites represented the major binding in layer III. They were also present in layers II and IV (29 and 24%) and, to a lesser extent, in layers V and VI. 5-HT1A sites were predominant in layer VI, II and V and were less abundant in other layers. 5-HT1D were homogeneously present in layers II, III, IV and were present in low amounts in other layers. No 5-HT1E were detected in choroid plexus, where [3H]5-HT was dramatically reduced by mesulergine (5-HT2C receptors). No significant displacement of [3H]5-HT by mesulergine was measured in other structures.  相似文献   

    19.
    We previously found different effects on behavior, serotonin (5-HT) concentrations, 5-HT uptake sites, and 5-HT1A binding sites of neonatal 5,7-dihydroxytryptamine (5,7-DHT) lesions depending on the route of 5,7-DHT injection. To study the impact of early lesions on 5-HT1B sites as putative 5-HT terminal autoreceptors, we labelled them autoradiographically with [3H]5-HT 4 months after intraperitoneal (i.p.) or intracisternal (i.c.) 5,7-DHT injection during the first postnatal week and quantitated specific binding in 22 brain regions. Changes were confined to the subiculum and substantia nigra, regions with the most 5-HT1B-specific binding and projection areas of structures with high mRNA expression. Both routes of 5,7-DHT injection were associated with increases in specific binding in subiculum (24% for i.p. and 47% for i.c. route). In contrast, there was a 32% increase in specific binding in the substantia nigra in rats with lesions made i.c. but not i.p. No significant differences were found in nucleus accumbens, caudate-putamen or other brain areas. In saturation homogenate binding studies of 5-HT1B sites using [125I]iodocyanopindolol 1 month after i.p. injections, neonatal 5,7-DHT lesions did not significantly alter Bmax or Kd in the neocortex, striatum, diencephalon or brainstem. These data indicate the differential effects of the route of neonatal 5,7-DHT injections on plasticity of 5-HT1B receptor recognition sites and suggest the presence of a subpopulation of post-synaptically located 5-HT1B sites which increases in response to denervation. The data also suggest that sprouting of 5-HT neurons after neonatal 5,7-DHT lesions does not involve 5-HT1B sites.  相似文献   

    20.
    Serotonin (5-HT) is a mediator (through 5-HT1P receptors) of slow EPSPs in myenteric ganglia of the small intestine. The effect of 5-HT can be mimicked by elevating cAMP; therefore, we tested the hypothesis that the slow EPSP-like response to 5-HT is cAMP-mediated. Guinea pig gut was enzymatically dissociated; myenteric ganglia remained intact and were collected by filtration. Neurons in the isolated ganglia retained their ability to manifest the slow EPSP-like response to 5-HT. Exposure to 5-HT raised the ganglionic level of cAMP (ED50 0.3 μM). This effect was not antagonized by the 5-HT1P antagonist, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (100.0 μM), or mimicked by the 5-HT1P agonist, 5-hydroxyindalpine (10.0 μM). Increases in cAMP were also evoked by the 5-HT1 agonist, 5-carboxyamidotryptamine (10.0 μM), the 5-HT2 agonist, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 1.0–10.0 μM), and by the 5-HT4 agonists, renzapride (1.0–10.0 μM) and 5-methoxytryptamine (1.0–10.0 μM); however, neither the 5-HT1/5-HT2 antagonists, spiperone, methysergide, and methiothepin, nor the 5-HT4 antagonist, tropisetron (ICS 205–930; 10.0 μM), were able to inhibit the rise in cAMP evoked by these compounds or by 5-HT (0.1–10.0 μM). The 5-HT-evoked elevation of cAMP was antagonized by ketanserin (10.0 μM), which also blocked the effects of 5-methoxytryptamine and DOI, but not those of renzapride. The effective concentration of DOI, however, was higher than that needed for activation of 5-HT2 receptors, and Northern analysis using a cDNA probe encoding the rat 5-HT2 receptor failed to reveal the presence of 5-HT2 mRNA in myenteric ganglia, although it hybridizes with mRNA of the right size in the guinea pig brain. Compounds that failed to change levels of cAMP or to antagonize the action of 5-HT included 8-hydroxy-di-n-propylamino tetralin, R58639, R88226, and sumatriptan. It is concluded that the receptor responsible for the 5-HT-induced rise in cAMP in ganglia isolated from the guinea pig myenteric plexus is not a known subtype of 5-HT receptor. Since the pharmacology of this novel receptor is different from that of the slow EPSP-like response to 5-HT, the receptor probably does not mediate the slow EPSP. © 1993 Wiley-Liss, Inc.  相似文献   

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