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91.
Rats were treated subchronically (14 days) or acutely (single dose) with the 1-selective adrenoceptor antagonist metoprolol or the 2-selective adrenoceptor antagonist ICI 118,551. Metoprolol (350 mg/kg/day for 14 days, orally) significantly reduced the 5-hydroxytryptophan (5-HTP) accumulation when measured 30 min after inhibition of L-amino acid decarboxylase by NSD 1015 (100 mg/kg IP) in the limbic forebrain, the corpus striatum, the cerebral cortex, the brain stem, and in the cerebellum. ICI 118,551 (0.5 mg/kg, twice daily for 14 days, SC) also significantly reduced the 5-HTP accumulation in the same brain regions except in the corpus striatum and the brain stem. Simultaneously assayed tryptophan levels were largely unaffected. Thus sustained -adrenoceptor blockade causes a decrease in the in vivo rate of tryptophan hydroxylation in various rat brain regions. The subchronic treatments with metoprolol or ICI 118,551 also significantly reduced the endogenous levels of 5-hydroxytryptamine (5-HT) in the various rat brain regions studied. Acute treatment with either metoprolol (2 mg/kg SC) or ICI 118,551 (0.5 mg/kg SC) did not affect the 5-HTP accumulation or the endogenous 5-HT levels in the brain regions studied. This inhibitory effect on brain 5-HT systems produced by sustained -adrenoceptor blockade may be of significance both for the long-term cardiovascular action and for occasional neuropsychiatric side effects during -blocking therapy. 相似文献
92.
Rats were trained to discriminate the stimulus properties of l-5-hydroxytryptophan (l-5-HTP) (30 mg/kg SC), the immediate precursor of serotonin (5-HT). The peripheral decarboxylase inhibitor R04-4602, administered prior to l-5-HTP, greatly attenuated the disruptive effects observed on responding when l-5-HTP alone was injected. Following acquisition, the discrimination was dosedependent and generalized to fenfluramine, a 5-HT-releasing drug, but not to amphetamine, a catecholamine-releasing agent. Further evidence for the involvement of 5-HT receptor stimulation in mediating the discrimination was that pretreatment with fluoxetine, a highly specific 5-HT uptake inhibitor, markedly potentiated the cue. Nevertheless, the classical 5-HT antagonists methysergide, cyproheptadine, metergoline, and methiothepin did not block the l-5-HTP-related discriminative stimulus. This finding suggested that the cue properties of l-5-HTP might be mediated by a population of 5-HT receptors previously identified electrophysiologically in limbic structures. As in the present experiment, the putative 5-HT antagonists did not block the synaptic effects of 5-HT in these structures. 相似文献
93.
Pretreatment with the MAO-inhibitors iproniazid, clorgyline, or deprenyl abolishes the effects of LSD on the conditioned avoidance response (CAR) in rats. The effects of serotonin (5-HT) and 5-methoxytryptamine (5-MT) are greatly potentiated by these substances. Brain levels of LSD are not affected by MAO inhibition whereas levels of 5-HT and 5-MT are significantly elevated. It is postulated that the decreased behavioral response to LSD is the result of MAO inhibitor-induced changes whereas the increased response of 5-HT and 5-MT results from increased brain levels of these compounds. 相似文献
94.
Quipazine, a serotonin receptor stimulant, inhibited the response of rats to painful stimuli in two methods currently used to measure antinociception in these animals: the hot plate and tail compression test. The antinociceptive action was observed with doses ranging from 5 to 20 mg/kg i.p. according to the test situation.The effect was significantly antagonized by a pretreatment with methergoline, a potent serotonin antagonist. An electrolytic lesion placed in the nucleus raphe medianus, which produced a marked decrease of serotonin in the forebrain did not, or only slightly, affected the effect of quipazine, depending on the method used to measure antinociception.It is suggested that quipazine can produce antinociceptive action in rats by interacting with a serotonergic mechanism. The action appears to be due mainly to a direct action on postsynaptic serotonin receptors, although a presynaptic component can also contribute to the effect of quipazine.Visiting scientist from Clinica Neurologica, UniversitàVisiting scientist from Clinica Neurologica, Università 相似文献
95.
Cocaine-induced convulsions appear to be mediated by serotonin (5-HT) neurotransmission, acting primarily at 5-HT(2) receptors. However, this effect of cocaine is attenuated by cocaine binding at sigma and muscarinic M(1) and M(2) sites. This study examined whether the aforementioned neural sites mediate the nearly two-fold difference in sensitivity to cocaine-induced convulsions across C57BL/6J (6J) and C57BL/6ByJ (6ByJ) mice. Experiment 1 compared 5-HT transporter densities across several brain regions of 6J and 6ByJ mice and cocaine-induced convulsions following pretreatment with the 5-HT reuptake inhibitor fluoxetine. Experiment 2 compared 5-HT(2) receptor densities across these mice and cocaine-induced convulsions following pretreatment with the 5-HT(2) antagonist cinanserin. There were no differences in 5-HT transporter densities, however, fluoxetine produced a greater facilitation of cocaine-induced convulsions in 6ByJ relative to 6J mice, suggesting that sensitivity to convulsions is mediated postsynaptically. Indeed, 5-HT(2) density was higher in 6ByJ relative to 6J mice in the amygdaloid ridge, hypothalamus, and midbrain. In addition, cinanserin attenuated convulsions more potently in 6J relative to 6ByJ mice. There were no differences in the densities or affinities of 5-HT(1), muscarinic, or sigma receptors across these strains, suggesting that density of these latter sites does not mediate genetic sensitivity to cocaine-induced convulsions. Since 6ByJ mice are less sensitive to convulsions despite the fact that they have more 5-HT(2) receptors, we hypothesized that these mice may exhibit a weaker linkage of 5-HT(2) sites to their second-messenger system relative to 6J mice. However, in experiment 3 we demonstrated that 5-HT(2)-receptor mediated phosphoinositide hydrolysis was higher in 6ByJ relative to 6J mice in the same regions also displaying higher 5-HT(2) densities. This study suggests that 5-HT(2) receptors mediate genetic sensitivity to cocaine-induced convulsions, further supporting the role of these sites in mediating this toxic effect of cocaine. 相似文献
96.
孕妇焦虑与去甲肾上腺素及5-羟色胺的关系 总被引:4,自引:0,他引:4
目的:探讨孕妇产前焦虑与去甲肾上腺素(NE)及5-羟色胺(5-HT)变化的关系。方法:选择择期剖宫产的孕妇80例,术前2 h孕妇自行填写汉密顿焦虑量表(HAS)、汉密顿抑郁量表(HDS)并对各项指标量化评分。根据评分分为无焦虑组(Ⅰ)、轻度焦虑组(Ⅱ)、中重度焦虑组(Ⅲ)3组。填表同时抽血测定NE、5-HT。结果:轻度焦虑组NE水平明显高于无焦虑组(P<0.01),中重度焦虑组NE水平明显高于无焦虑组(P<0.01),与轻度焦虑组无显著性差异(P>0.01)。轻度焦虑组5-HT水平明显低于无焦虑组(P<0.01),中重度焦虑组5-HT水平明显低于无焦虑组和轻度焦虑组(P<0.01)。孕妇焦虑程度与NE呈正相关(r=0.538,P<0.01),与5-HT呈负相关(r=-0.570,P<0.01)。结论:NE、5-HT在孕妇产前焦虑情绪的发生过程中起着重要的作用。 相似文献
97.
目的研究胃窦肌间神经丛中单胺氧化酶mRNA表达,探讨5羟色胺(5-HT)在胃起搏机制中的作用。方法通过手术建立Wistar大鼠胃起搏模型(近远端胃各缝制一对电极),分为起搏组(n=10)和对照组(n=6)。采用逆转录聚合酶链反应(RT-PCR)检测起搏组和对照组胃窦肌间神经丛中MAO-A mRNA、MAO-B mRNA的表达量,以恒定表达的β-actin作为内参照。计算MAO-AmRNA、MAO-B mRNA与β-actin mRNA表达积分光密度值的比例(MA/B,MB/B),以反映组织中MAO-AmRNA、MAO-B mRNA的相对表达量。结果RT-PCR研究显示起搏组MAO-A mRNA表达显著弱于对照组,起搏组MA/B比值明显较对照组较少(0.37±0.11vs0.95±0.57,P<0.001);而起搏组MAO-B mRNA表达与对照组无差别,两组间MB/B比值比较也无显著性意义(0.97±0.24vs1.01±0.58,P>0.05)。结论胃起博后胃肌间神经丛内单胺氧化酶mRNA表达量明显减少,表明胃窦肌间神经丛内5-HT可能在胃起搏中发生了重要作用。 相似文献
98.
N. Limberger M. R. G. Fischer T. Wichmann K. Starke 《Naunyn-Schmiedeberg's archives of pharmacology》1989,340(1):52-61
Summary Possible antagonist effects of phentolamine at presynaptic serotonin autoreceptors were studied in slices of the occipito-parietal cortices of the rabbit and the rat. The slices were preincubated with 3H-serotonin and then superfused and stimulated electrically with single pulses or pulse trains. Nitroquipazine 1 mol/l, a compound that inhibits the high affinity neuronal uptake of serotonin, was present in the superfusion medium in all one pulse-experiments as well as in experiments in which the effect of unlabelled serotonin was examined.In rabbit cortical slices, unlabelled serotonin reduced the single pulse-evoked overflow of tritium. Its concentrationresponse curve was not changed by the selective 2-adrenoceptor antagonist idazoxan 1 mol/l but was shifted to the right by phentolamine 1 and 10 mol/l. Phentolamine 10 mol/l also shifted to the right the concentration-inhibition curve of the selective 5-HT1-receptor agonist 5-carboxamidotryptamine. When the slices were stimulated by trains of 30 pulses at 3 Hz, phentolamine 1 and 10 mol/l but not 0.1 mol/l increased the evoked overflow of tritium, the maximal increase amounting to 178%; its effect was enhanced in the presence of nitroquipazine 1 mol/l plus idazoxan 10 mol/l (a drug combination that, when given alone, slightly increased the evoked overflow of tritium). The serotonin receptor antagonist metitepin at concentrations of 0.01–1 mol/l also increased the overflow of tritium elicited by 30 pulses/3 Hz, the maximal increase amounting to 280%; its effect was potentiated in the presence of nitroquipazine 1 mol/l plus idazoxan 10 mol/l but was abolished or almost abolished in the presence of nitroquipazine 1 mol/l plus phentolamine 10 mol/l (a drug combination that, given alone, greatly increased the evoked overflow of tritium). When slices were stimulated by trains of 360 pulses at 3 Hz, there was no apparent antagonism of phentolamine 10 mol/l against the inhibitory effect of unlabelled serotonin. In rat brain cortex slices, unlabelled serotonin reduced the overflow of tritium elicited by 4 pulses delivered at 100 Hz. Again, phentolamine 10 mol/l shifted the concentration-response curve to the right.It is concluded that phentolamine blocks presynaptic serotonin autoreceptors in rabbit and rat brain cortex with pA2 values of 6.44 and 5.95, respectively. Previous failures to detect the antagonistic effect against exogenous agonists were probably due to stimulation conditions that led to marked endogenous autoinhibition of serotonin release. At least the major part of the increase by phentolamine of the release of serotonin is due to autoreceptor blockade rather than blockade of the presynaptic a2-adrenoceptors at the cortical serotoninergic axons.Send offprint requests to N. Limberger at the above address 相似文献
99.
The effects of para-chlorophenylalanine pre-treatment (PCPA, 150 mg/kg IP daily for 3 days) on feeding and stereotyped behaviour
elicited by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in rats were investigated. PCPA depleted brain serotonin and 5-hydroxyindoleacetic acid
concentrations by 90% and increased feding during a 2-h day-time test. 8-OH-DPAT (60–4000 μg/kg SC) increased food intake
in control animals but decreased in in PCPA-treated animals during the 2-h test. PCPA treatment had no effect on 8-OH-DPAT-induced
locomotion or serotonin-related stereotyped behaviour (i.e. forepaw treading, headweaving, wet dog shakes, etc). Since PCPA
prevents the operation of pre-synaptic serotonergic mechanisms, the failure of 8-OH-DPAT to increase food intake in PCPA-treated
rats suggests that 8-OH-DPAT-induced hyperphagia is autoreceptor mediated. 相似文献
100.
Suzanne M. Evans Alphonse Galdes Martin Gall 《Pharmacology, biochemistry, and behavior》1991,40(4):1033-1040
Ligands of various chemical classes (e.g., indoles, indazoles, benzamides, carbazoles, and quinolines) have demonstrated high affinity for the 5-HT3 receptor in radiolabeled ligand-binding studies, and have shown 5-HT3 receptor antagonistic activity in functional assays which utilize the excitatory effects of 5-HT on enteric neurons and autonomic afferents. Several 5-HT3 antagonists are currently being evaluated for potential use in the treatment of migraine, schizophrenia, and anxiety, and a few have already demonstrated high efficacy as antiemetics in cancer chemotherapy. The purpose of this presentation is to highlight the significant structure-affinity relationships (SAFIR) and common geometrical features among 5-HT3 receptor ligands, and to describe the three-dimensional pharmacophore for the 5-HT3 recognition site derived from computational techniques. The chemical template containing the recognition elements (functional groups) for the 5-HT3 receptor are: an aromatic or heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center, interrelated by well-defined distances. Two “binding shapes” or “active shapes” for 5-HT3 ligands have been identified from detailed conformational analyses. 相似文献