Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00530 (Portal)
 4,208 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in insulin and glucagon levels might account for the plasma amino acid imbalance of cirrhotics. In order to verify this hypothesis we evaluated basal insulin, glucagon, branched-chain amino acids, aromatic amino acids, and free tryptophan in 13 controls and 37 cirrhotics divided on the basis of their mental state; in 4 patients the hormonal and amino acid patterns were sequentially studied during various stages of encephalopathy. Glucagon is high in cirrhotics and progressively increases with the worsening of the mental state. Free tryptophan and aromatic amino acids show a similar behavior and significantly correlate with glucagon levels (r = 0.67 and r = 0.81, respectively). On the other hand insulin levels, which are high in cirrhotics without encephalopathy, fall in the presence of deep coma. Insulin did not correlate with any of the plasma amino acids considered. Our data suggest that the catabolic state associated with increased glucagon levels may account for some of the alterations in the plasma amino acid profiles of cirrhotics. Portal-systemic shunting does not seem to be the common cause of both hyperglucagonemia and hyperaminoacidemia. Decreased branched-chain amino acid levels may be related to factors different from those involved in the alterations of carbohydrate homeostasis.
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PMID:Insulin and glucagon levels in liver cirrhosis. Relationship with plasma amino acid imbalance of chronic hepatic encephalopathy. 46 10

The effects of fenfluramine and other sanorectic drugs on the consumption of both protein and total calories by rats given simultaneous access to two isocaloric diets containing 5 or 45 percent casein were examined. Anorectic doses of fenfluramine failed to decrease protein intake but increased the proportion of total dietary calories represented by protein. In contrast, anorectic doses of d-amphetamine decreased protein and calorie consumption proportionately. Subanorectic doses of fenfluramine also increased the proportion of caloric intake represented by protein among animals given prior treatment with the serotonin precursor tryptophan. Fluoxetine, a drug that blocks reuptake of serotonin, similarly spared protein consumption while reducing caloric intake. These observations indicate that two distinct brain mechanisms, sensitive to different drugs, underlie the elective consumption of protein and calories.
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PMID:Fenfluramine and fluoxetine spare protein consumption while suppressing caloric intake by rats. 92 95

The inter-renal (adrenal) gland of amphibians is composed of chromaffin and steroidogenic cells which can interact through a paracrine mode of communication. We have previously shown that serotonin is present in secretory granules of frog adrenochromaffin cells; concurrently, we have demonstrated that serotonin is a potent stimulator of corticosterone and aldosterone secretion by adrenocortical cells. The aim of the present study was to determine the origin of the amine contained in frog chromaffin cells. Using 3H-labelled tryptophan as a precursor, we observed the formation of substantial amounts of serotonin and its metabolite 5-hydroxyindoleacetic acid by frog inter-renal slices. Newly synthesized serotonin was secreted into the incubation medium and the release process was enhanced by depolarizing concentrations of KCl. Fluoxetine, and inhibitor of serotonin uptake, caused an increase of 3H-labelled serotonin in the incubation medium, suggesting that the indoleamine was taken up again by adrenal chromaffin cells. The capacity of the frog inter-renal gland to synthesize serotonin was also demonstrated by incubating inter-renal slices with non-labelled tryptophan or 5-hydroxytryptophan. In these conditions, we observed that the rate of synthesis was higher when 5-hydroxytryptophan was used as a a precursor, rather than tryptophan. Taken together, these results indicate that chromaffin cells, which have the capacity for synthesizing and releasing serotonin, behave like authentic serotonergic paraneurons. As far as is known, these data provide the first evidence for the occurrence of tryptophan-5-hydroxylase activity within the adrenal gland.
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PMID:Serotonin synthesis in adrenochromaffin cells. 137 54

Electroencephalographic sleep was quantitated in adult male Sprague-Dawley rats following single injections of the methylesters of tryptophan, valine or alanine. The amino acids were administered at the onset of the daily light period (09.00 h); electrographic data were collected for the succeeding 6-h period. Saline served as the injection control, and fluoxetine, a serotonin-reuptake blocker, as a positive control. The injection of tryptophan methylester (125 mg/kg) caused a delay in rapid eye movement (REM) sleep onset, and significantly reduced the amount of REM sleep during the first 2 h postinjection. Tryptophan produced no effect on sleep onset, nor did it influence total sleep time. Fluoxetine (2.5 mg/kg) produced similar effects, as previously observed. The methylesters of valine and alanine were without effect on REM sleep, when injected at a molar dose equivalent to that for tryptophan. No consistent effects of any of the test substances were noted on non-REM (NREM) sleep or waking time, or on any of the other sleep indices quantitated. Together, the data indicate that tryptophan selectively reduces REM sleep; the effect is not due to a non-specific action of amino acids or their methylesters. The effect on REM sleep may be the consequence of a tryptophan-induced stimulation of 5-HT synthesis and release, since it is like that produced by fluoxetine, a drug that enhances transmission across serotonin synapses.
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PMID:Effects of L-tryptophan and other amino acids on electroencephalographic sleep in the rat. 227 29

We compared the effects of CGS 10686B (a new drug that blocks serotonin reuptake), on nutrient selection and total food consumption with those of two other serotoninergic drugs, dl-fenfluramine and fluoxetine. The animals were given simultaneous free access to two isocaloric 40%-carbohydrate diets in separate food pans; one of these diets (5% protein) was shown to enhance brain serotonin synthesis by raising brain tryptophan levels; the other (45% protein) did not. CGS 10686B (4-7.5 mg/kg) markedly decreased (60-70%) consumption of the 5% protein diet, with a smaller effect (20-30%) on consumption of the 45% protein diet. Hence, it increased the ratio of protein to carbohydrate in the total food consumed. Higher doses (12.5-15 mg/kg) were no longer nutritionally-specific. Fluoxetine, which also blocks serotonin reuptake, and dl-fenfluramine, which both releases serotonin and suppresses its reuptake, had similar effects on nutrient intake; dl-fenfluramine was most potent and fluoxetine least. None of the drugs selectively affected carbohydrate or protein intake if the composition of the test diets provided was such that neither diet, eaten alone, would increase brain serotonin. These observations affirm that drugs which enhance serotoninergic neurotransmission selectively suppress the intake of high-carbohydrate, low-protein meals which increase brain serotonin synthesis.
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PMID:Selective effects of CGS 10686B, dl-fenfluramine or fluoxetine on nutrient selection. 283 55

In previous studies tryptophan and 5-hydroxy-tryptophan (5-HTP) treatments produced opposite effects on aggression and vigilance and differing effects on eating and locomoting in vervet monkeys. This study examined the effects of the serotonin reuptake inhibitor fluoxetine, and the catecholamine reuptake inhibitor desmethylimipramine (DMI) on tryptophan and 5-HTP induced behavioral changes. Thirty-two adult males from 16 different social groups were studied. Tryptophan (10, 20, and 40 mg/kg/day) produced dose-dependent reductions in aggression, vigilance, and locomotion and increases in eating. In contrast, 5-HTP (20, 40, and 80 mg/kg/day) increased aggression and vigilance and did not affect locomotion or eating. Fluoxetine (0.5, 1.0, and 2.0 mg/kg/day) produced effects identical to tryptophan while DMI (1.5, 3.0, and 6.0 mg/kg/day) resulted in dose-dependent increases in aggression, vigilance, and locomotion, and decrements in eating. When combined with tryptophan, fluoxetine augmented and DMI diminished the effects of tryptophan on all behaviors. Fluoxetine decreased and DMI increased the effects of 5-HTP on aggression and vigilance. Thus concurrent DMI enhanced and concurrent fluoxetine reduced the differences between 5-HTP and tryptophan. These results suggest that 5-HTP's effects on catecholaminergic systems may underlie the differing behavioral effects of tryptophan and 5-HTP on behavior in a species closely related to humans.
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PMID:Differential behavioral effects of tryptophan and 5-hydroxytryptophan in vervet monkeys: influence of catecholaminergic systems. 311 14

In vivo voltammetry enables catecholamine and 5-hydroxytryptamine (5-HT) release to be directly determined in the brains of conscious unrestrained animals. This study concerned the validation of the measurement of 5-HT release using scanning voltammetry at chronically implanted carbon paste/epoxy resin glass microelectrodes in the rat hippocampus. Automated recordings of the current produced by applying a ramp (100 mV/s) potential (0-1 V) to the electrode at 5 min intervals were made over a period of several hours. A current peak at 0.35-0.4 V corresponded to that produced by solutions of 5-HT in vitro. The effect of a number of drug known to affect 5-HT synthesis and release was then studied in vivo. p-Chloroamphetamine (PCA) caused an increase in the peak which correlated with a '5-HT behavioural syndrome'. p-Chlorophenylalanine caused a reduction in the peak and prevented both the increase seen with PCA and the PCA induced behavior. Fluoxetine and L-tryptophan also led to increases in signal; all these results were consistent with the signal reflecting extraneuronal 5-HT. However 5-hydroxyindoleacetic acid (5HIAA) also oxidizes at 0.35-0.4 V in vitro. Probenecid, which blocks 5HIAA egress from the brain caused a large increase in the hippocampal signal. The monoamine oxidase inhibitors pargyline and nialamide, which increases 5-HT and reduce 5HIAA levels, had no significant effect on the signal. These results, together with the greater increase in signal following probenecid than tryptophan and the delayed increase after tryptophan, and interpreted as implying that extraneuronal 5HIAA and 5-HT contribute approximately equally to the hippocampal signal. We conclude that this method gives information distinct from and complementary to biochemical estimations, and offers great scope for the investigation of the role of 5-hydroxyindole release in drug and environmental effects on behaviour.
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PMID:Does in vivo voltammetry in the hippocampus measure 5-HT release? 646 87

In vivo rates of 5-hydroxytryptophan accumulation (following administration of the decarboxylase inhibitor R04/4602/1) and levels of 5-HT in the nucleus raphe dorsalis (DR), nucleus centralis superior (NCS), nucleus septalis lateralis (LS), nucleus suprachiasmaticus (SCN), nucleus hypothalamicus anterior (AH), and nucleus amygdaloideus centralis (AG) were determined following administration of fluoxetine, 5-methoxy-N,N-dimethyltryptamine, methiothepin, L-tryptophan and reserpine. Fluoxetine and 5-methoxy-N,N-dimethyltryptamine inhibited 5-hydroxytryptophan synthesis in all nuclei, although inhibition of synthesis in the DR was resistant to fluoxetine. Methiothepin inhibited 5-HT synthesis in the DR, NCS, LS and AG, but not in the SCN or AH. L-Tryptophan greatly increased 5HT synthesis in all areas, but this increase was not uniform, being fourfold greater in the NCS than in the LS. Reserpine, while greatly depleting 5HT did not increase 5-hydroxytryptophan synthesis in any nucleus. In no region could changes in brain tryptophan account for the observed drug effects on serotonin metabolism. We conclude that not all CNS serotonergic structures respond to the same drug in a uniform manner.
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PMID:Regional differences in the response of serotonergic neurons in rat CNS to drugs. 660 57

Animals in which 5,7-dihydroxytryptamine (5,7-DHT) was bilaterally injected into the median forebrain bundle (MFB) and sham lesioned animals were allowed access to an apparatus which delivered, upon lever pressing, intravenous D-amphetamine injections. MFB lesioned rats achieved stable self-injections patterns and self-administered more drug per test session than controls. A number of agents known to either directly or indirectly affect 5-hydroxytryptamine (5-HT) receptor function were administered prior to D-amphetamine access. The responses to these pretreatments in lesioned vs non-lesioned rats were markedly different. Pretreatment with L-tryptophan reduced the number of D-amphetamine self-injections in sham lesioned rats but had no effect in MFB lesioned animals. Fluoxetine pretreatment, likewise, reduced responding in non-lesioned rats and had no observable effect in lesioned animals. Quipazine markedly reduced self-injection in control rats but was not evaluated in the lesioned group. The putative 5-HT antagonists utilized, cyproheptadine and methysergide, unpredictably reduced self-injection frequency of non-lesioned animals in a dose related manner. When MFB lesioned animals were pretreated with cyproheptadine, rapid bursts of lever pressing were observed and 3 of 6 animals thus treated died as a result (presumably amphetamine overdose). In the remaining animals, methysergide produced a similar marked increase in self-injection rate. While these data may suggest that, in some instances, non-serotonergic mechanisms are involved, for the most part it would appear that 5-HT containing neurons are of major import in some aspect of D-amphetamine self-administration.
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PMID:The effects of putative 5-hydroxytryptamine receptor active agents on D-amphetamine self-administration in controls and rats with 5,7-dihydroxytryptamine median forebrain bundle lesions. 661 Apr 61

Fluoxetine alone enhances central serotonin function as measured by a variety of test systems and potentiates the effects of serotonin precursors. Table 1 lists various effects of tryptophan or 5HTP that have been potentiated by fluoxetine. This potentiation or synergistic interactions between fluoxetine and L-5HTP constitute excellent evidence that any given effect is influenced by a serotonin synaptic connection.
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PMID:Functional consequences of inhibiting serotonin uptake with fluoxetine in rats. 675 12


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