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1.
Lesions in the medial forebrain bundle of the rat produced a 68 to 74% decrease in telencephalic serotonin (5-HT) and a 30 to 43% decrease in jump threshold. L-5-Hydroxytryptophan (L-5-HTP; 37.5 mg/kg) returned the 5-HT content and jump threshold of lesioned rats to normal levels. These effects of L-5-HTP were also observed after the inhibition of extracerebral decarboxylase activity with Ro 4-4602 (50 mg/kg). Pretreatment with 6-hydroxydopamine (6-OHDA), which selectively destroys catecholamine neurons, had no effect on the jump threshold of nonlesioned rats nor did it further change the 5-HT content or jump threshold of lesioned rats. Lesioned rats pretreated with 6-OHDA demonstrated an increase in 5-HT content after L-5-HTP; however, their jump threshold remained significantly lower than that of controls. This ability of 6-OHDA to block the behavioral effects of L-5-HTP in lesioned rats was also observed after Ro 4-4602. In rats given Ro 4-4602, the accumulation of 5-HT at 90 minutes after injection of L-5-HTP was significantly correlated (r = 0.98) with total monoamine content. Thus, 6-OHDA pretreatment significantly decreased the net accumulation of 5-HT from L-5-HTP in nonlesioned rats. These rats also demonstrated further decreases in norepinephrine and dopamine content after L-5-HTP. It was concluded that L-5-HTP can be decarboxylated to 5-HT in serotonergic and catecholaminergic neurons and that the behavioral effects of L-5-HTP in lesioned rats may be due to the formation of 5-HT in catecholaminergic neurons where it may act as a "false-transmitter."  相似文献   

2.
3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a known neurotoxin to 5-hydroxytryptamine (5-HT; serotonin) nerve terminals. It has recently been demonstrated that [3H]6-nitroquipazine is a new radioligand for studying the 5-HT transport system in brain. Therefore, we examined the effects of repeated systemic administration (10 mg/kg ip, twice daily for 3 d) of MDMA on [3H]6-nitroquipazine-labelled 5-HT uptake sites in rat brain. Marked reductions in the concentrations of 5-HT and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) were observed in the cerebral cortex 1 week after the last injection of MDMA. In addition, the density of [3H]6-nitroquipazine-labelled 5-HT uptake sites was significantly decreased by MDMA. Furthermore, the reduction of 5-HT and 5-HIAA content and the density of [3H]6-nitroquipazine-labelled 5-HT uptake sites by MDMA were significantly prevented by co-administration of 6-nitroquipazine (5 mg/kg), a very potent and selective 5-HT uptake inhibitor. The present results indicate that the 5-HT uptake carrier plays an important role in the neurotoxic action of MDMA.  相似文献   

3.
In rats with a portacaval shunt (PCS), the effect on the serotonin metabolism in the brain after oral administration of blood, a mixed amino acid solution (Vamin 14; KabiVitrum, Sweden) or a 10% glucose solution was studied. One week after PCS, the animals were fed with a gastric tube for 8 h and thereafter tested for behavioral abnormalities before decapitation at 12 h. The concentration of 5-hydroxytryptophan (5-HTP), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were analyzed chromatographically (HPLC technique with electrochemical detection) in different regions of the brain. Estimation of synthetic rates of 5-hydroxyindoles was facilitated by aromatic aminoacid decarboxylase inhibition (m-hydroxybenzyl-hydrazine; NSD 1015). The brain concentrations of 5-HTP, 5-HT, and 5-HIAA were increased in all shunted rats as compared with sham-operated animals. Whether animals received blood, glucose, or aminoacid solution made no differences in the brain concentrations of 5-HTP and 5-HT. Concentrations of 5-HIAA were lower in those animals receiving blood as compared with the other shunted groups. No reproducible differences in the behavior of the animals were observed. These results suggest that massive blood administration 1 week after PCS in rats has no influence on the rate of brain indole synthesis. While alterations in serotonin metabolism may play a role in some forms of encephalopathy, this study implies that the behavioral and neurologic disorders which follow gastrointestinal tract hemorrhage in patients with liver failure may have other etiologies.  相似文献   

4.
The serotonin (5-HT) receptor-related compounds metergoline, pirenperone, ketanserin, cyproheptadine, pizotyline, methysergide, lysergic acid diethylamide, mianserin and cinanserin were studied in pigeons trained to discriminate l-5-hydroxytryptophan (l-5-HTP) (18.0 mg/kg) from saline and in pigeons trained to discriminate quipazine (1.0 mg/kg) from saline. Metergoline did not generalize to either quipazine or l-5-HTP but did antagonize drug-appropriate responding in both groups. Ketanserin potently blocked the quipazine discriminative stimulus and neither generalized to nor attenuated the l-5-HTP discriminative stimulus. Pirenperone, cinanserin, cyproheptadine, methylsergide, pizotyline and mianserin attenuated the quipazine discriminative stimulus at low doses and, at higher doses, generalized to the l-5-HTP discriminative stimulus. No antagonism of the l-5-HTP-discriminative stimulus or generalization to the quipazine-discriminative stimulus were observed with these compounds. A correlation coefficient of 0.93 was calculated between the potencies of 5-HT compounds to generalize to the l-5-HTP stimulus and the binding affinities of these compounds for a 5-HT1 receptor in rat brain. In addition, a correlation coefficient of 0.78 was calculated between the potencies of 5-HT compounds to attenuate the quipazine stimulus and the binding affinities of these compounds for the 5-HT2 receptor in rat brain. These observations suggest cyproheptadine, pizotyline, methysergide, lysergic acid diethylamide, mianserin and cinanserin are agonists at the 5-HT1 receptor in the l-5-HTP discrimination and antagonists at a 5-HT2 receptor in the quipazine discrimination in pigeons.  相似文献   

5.
The 5-hydroxytryptamine (serotonin; 5-HT) agonists, RU-24969 [5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H-indole, succinate], ipsapirone [2-(4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl)-1,2- benzisothiazol-3-(2H)one-1,1-dioxidehydrochloride], 8-hydroxy-N,N-dipropyl-2-aminotetralin, lysergic acid diethylamide, fenfluramine and N,N-dimethyltryptamine were studied in pigeons trained to discriminate quipazine (1.0 mg/kg) from saline and in pigeons trained to discriminate I-5-HTP (18.0 mg/kg) from saline. Lysergic acid diethylamide, quipazine and fenfluramine generalized to the training stimulus in both groups of pigeons. N,N-dimethyltryptamine generalized to quipazine in all pigeons tested whereas N,N-dimethyltryptamine generalized to I-5-HTP in most pigeons tested. The natural substrate 5-HT and agonists with affinities for the 5-HT1 receptor and its subtypes (8-hydroxy-N,N-dipropyl-2-aminotetralin, ipsapirone, and RU-24969) only generalized in the I-5-HTP-trained pigeons. Equilibrium binding experiments using the ligands [3H]-5-HT and [3H]ketanserin were performed with six areas of pigeon brain and six homologous areas of rat brain. Two populations of 5-HT binding sites were found in brains of both species; one defined by high-affinity binding of [3H]-5-HT and the other defined by high-affinity binding of [3H]ketanserin. Kd values were similar for the two ligands in brains of both species. 5-HT, RU-24969 and ipsapirone displaced [3H]-5-HT but not [3H]ketanserin from pigeon brain membranes. The present study suggests that, in the pigeon, the 5-HT2 receptor might mediate the discriminative-stimulus effects of quipazine, whereas the 5-HT1 receptor might mediate the effects of I-5-HTP.  相似文献   

6.
The cotton pellet technique was used to evaluate the effect of 5-HT and certain related compounds on granuloma formation in the rat. 5-HT (10 mg/kg) significantly decreased granuloma formation, significantly increased adrenal weight, and significantly decreased thymus weight in normal rats, and significantly decreased granuloma formation and thymus weight in sham-operated rats. On the other hand, 5-HT (10 mg/kg) significantly increased granuloma weight in adrenalectomized rats. Methysergide (1 mg/kg) blocked the inhibitory effect of 5-HT on granuloma formation as well as the changes in weight of adrenal and thymus glands. 5-HIAA (11 mg/kg) and 5-HTP (13 mg/kg) failed to alter granuloma formation.  相似文献   

7.
Buspirone, an anxiolytic drug with selective affinity for the 5-HT-1A subtype of serotonin receptors, caused a dose-related decrease in 5-hydroxyindole acetic acid (5-HIAA) concentration in rat hypothalamus after doses of 1 to 10 mg/kg s.c. The decrease in 5-HIAA concentration after a 3 mg/kg s.c. dose of buspirone persisted at 4 hr but not at 7 hr. The decrease was due apparently to a reduced turnover of serotonin; the accumulation of 5-hydroxytryptophan after decarboxylase inhibition was also suppressed by buspirone, not only in hypothalamus but also in brain stem, hippocampus and striatum. 1-(2-Pyrimidinyl)-piperazine (1-PP), a major metabolite of buspirone, did not affect hypothalamic 5-HIAA concentration at doses up to 10 mg/kg s.c. Both buspirone and 1-PP increased hypothalamic concentrations of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) sulfate, the norepinephrine metabolite, the effect being more pronounced with 1-PP but occurring after doses as low as 0.3 mg/kg s.c. with each compound. The increase in MHPG sulfate concentration persisted for at least 4 hr after a 3 mg/kg s.c. dose of each compound. The increase in MHPG sulfate produced by buspirone may have been due partly to 5-HT-1A receptor activation, inasmuch as other serotonin agonists have been found to cause a similar increase. 1-PP is reported to lack affinity for 5-HT-1A receptors so its elevation of MHPG sulfate concentration may have resulted from alpha-2 receptor blockade. The increase in MHPG sulfate concentration after buspirone injection may have been due at least partly to formation of the metabolite, 1-PP.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

8.
The role of serotonin in the effect of amphetamine on the firing rate of midbrain dopaminergic neurons was examined using unit recordings of identified A10 dopamine neurons in the chloral hydrate-anesthetized rat. Amphetamine (1 mg/kg, i.v.) reduced the firing rate of these neurons approximately 50 to 60%. This effect was blocked in animals pretreated with the selective serotonin-2 (5-HT2) receptor antagonists, MDL 28,133A (0.2 mg/kg, i.v.) or ritanserin (1 mg/kg, i.v.). Although pretreatment with L-dopa (100 mg/kg, i.v.) plus carbidopa (25 mg/kg, i.p.) alone had no effect on amphetamine-induced slowing of A10 dopamine neurons, when coadministered with the 5-HT2 antagonists, the dopamine precursor completely restored this amphetamine-induced slowing. To verify the role of serotonin in these findings, rats were pretreated with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine (250 mg/kg/day for 2 days) to deplete cortical serotonin levels. Consistent with the results observed with the 5-HT2 receptor antagonists, amphetamine did not produce a significant reduction in the firing rate of A10 neurons in serotonin-depleted rats. These results suggest that, under some conditions, serotonergic input via the activation of 5-HT2 receptors may regulate the availability of the pool of dopamine, which is subject to amphetamine release.  相似文献   

9.
After intraperitoneal application of the antiepileptics dipropylacetamide (DPM, 200 mg/kg) and dipropylacetic acid (DPA, 200 mg/kg) in mice their concentration in plasma and their effects on 5-hydroxytryptamine (5-HT) metabolism in the brain were followed during 360 minutes. Peak plasma level of DPA and DPM was observed at 30 minutes, but level of DPM was only about 25% that of DPA. Plasma content of both drugs declined to low levels by 360 minutes. Both drugs increased brain content of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA). After DPA application 5-HIAA level increased rapidly and had returned to control value by 360 minutes, while following DPM 5-HIAA increase was much more gradual and was more prolonged. Neither DPM nor DPA significantly altered brain 5-HT content. An apparent relationship between DPA plasma level and brain 5-HIAA content was observed while after DPM no association between plasma drug content and effect on cerebral 5-HT metabolism was seen.  相似文献   

10.
Subtotal or total liver ischaemia was induced in the rat by dividing the hepatic artery (Expt. I) or by total dearterialisation of the liver (Expt. II) 2 days after porta-caval shunt (PCS). The animals received i.v. a 10% glucose infusion for 5 h after the last operation and were killed by decapitation. At the end of the experiment all animals with liver ischaemia were in Grade III coma. In different regions of the CNS 5-hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), were analysed by HPLC-technique with electrochemical detection, while dihydroxyphenylalanine (DOPA), dopamine (DA) and norepinephrine (NE) were analysed with a radio enzymatic method after blocking the decarboxylation of 5-HTP to 5-HT and DOPA to DA by inhibition of the aromatic amino acid decarboxylase enzyme with m-hydroxybenzylhydrazine (NSD 1015) in order to estimate the synthesis rate of 5-hydroxyindoles and catecholamines. In Expt. I concentrations of 5-HTP in animals with PCS were increased as compared to sham operation. In animals with liver ischaemia, 5-HTP concentrations were increased as compared to sham operation but similar to those in animals with PCS alone. These results suggest that ligation of the hepatic artery for 5 h in PCS animals does not further accelerate the rate of brain indole synthesis. In Expt. II, the 5-HTP concentrations were increased in PCS animals as compared to sham operation. Animals with total liver dearterialisation exhibited decreased 5-HTP levels as compared to PCS, suggesting a decreased brain indole synthesis after severe liver ischaemia. In Expt. II, CNS concentrations of DOPA following PCS were unaltered as compared with sham-operated animals. In animals with total liver dearterialisation, DOPA levels were increased, suggesting an augmented catecholamine synthesis. The NE levels were lower than in PCS and in sham-operated animals.  相似文献   

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