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)

The present experiments were designed to test the hypothesis that the long-term effects of p-chloroamphetamine (PCA) on serotonergic neurons in rats are mediated by a neurotoxic metabolite. The effects of well-known inducers and an inhibitor of hepatic microsomal drug-metabolizing enzymes on the PCA-induced decreases in brain levels of 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase activity and the half-life of PCA in brain were examined. All of these modified the half-life of PCA in a predictable manner: 3-methylcholanthrene and, to a much lesser extent, phenobarbital decreased the half-life of PCA while piperonyl butoxide markedly increased it. Fluoxetine, an inhibitor of 5-HT uptake, also increased the half-life of PCA in brain. In addition, fluoxetine blocked the long-term effects of PCA on 5-HT levels and tryptophan hydroxylase activity. Of the classical metabolic tools, only 3-methylcholanthrene provided complete protection from the long-term, neurotoxic effects of PCA. Although the mechanism of this protection is unknown, it is not mediated by a blockade of 5-HT uptake since 3-methylcholanthrene did not decrease the synaptosomal uptake of 5-HT. Piperonyl butoxide pretreatment markedly increased the half-life of PCA in brain, but it failed to modify consistently the effects of PCA. The results indicate that the long-term, neurotoxic effects of PCA are not mediated by the major, hepatic metabolites of the drug, but leave open the possibility of a minor, neurotoxic metabolite.
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PMID:Long-term reduction of brain serotonin by p-chloroamphetamine: effects of inducers and inhibitors of drug metabolism. 68 26

Repeated administration of large doses of d-methamphetamine produce long-lasting depletion of brain dopamine (DA) and serotonin (5-HT), as well as persistent decreases in the activity of their respective biosynthetic enzymes, tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH). The present results indicate that the inhibitor of 5-HT uptake fluoxetine, prevented the long-term depletion of 5-HT produced by large doses of methamphetamine (15 mg/kg X 5, 6 hr apart) in the neostriatum and hippocampus, while simultaneously augmenting the depletion of DA produced by this drug in the neostriatum. Fluoxetine also enhanced the prolonged neostriatal depletion of DA produced by a comparable regimen of d-amphetamine. In these doses (15 mg/kg X 5,6 hr apart), d-amphetamine did not produce long-lasting depletion of 5-HT in either the neostriatum or hippocampus. Larger depletion of DA after the amphetamines had been administered in the fluoxetine pretreated animal were associated with a transient increase in the brain levels of methamphetamine and amphetamine. This suggests that fluoxetine may inhibit the metabolism of amphetamines.
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PMID:Fluoxetine increases long-lasting neostriatal dopamine depletion after administration of d-methamphetamine and d-amphetamine. 660 37

Fragments of adult rat pancreas were incubated in vitro with tritiated serotonin at concentrations from 10(-8) to 10(-7) M. The pancreas exhibited an uptake of serotonin which was saturable, with an uptake constant (Km) of 8.75 x 10(-7) M, and a Vmax of 873 pmoles per gram. Specificity was determined by the addition of fluoxetine or norepinephrine to the reaction mixture, both at 10(-5) M. Fluoxetine significantly reduced the 3H-5HT uptake, whereas norepinephrine was without effect. Metergoline (10(-6) M), a specific 5-HT postsynaptic receptor blocker, similarly had no effect on the serotonin uptake in the pancreas. Radioautography of the fragments following uptake of tritiated serotonin (5 x 10(-8) M) revealed silver- grain aggregates dispersed along blood vessels in the interstitial spaces of the exocrine and endocrine pancreas, areas known to be traversed by nerve fibers. There were no silver- grain aggregates over the exocrine or islet parenchymal cells. These data support the hypothesis that the pancreas is innervated by serotonergic fibers. Further evidence for this hypothesis was provided by a preliminary study demonstrating the presence of tryptophan hydroxylase in pancreatic homogenates. These serotonergic fibers may be involved in the regulation of pancreatic secretion.
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PMID:Specific uptake of tritiated serotonin in the adult rat pancreas: evidence for the presence of serotonergic fibers. 697 Oct 51

Methamphetamine-induced 5-hydroxytryptaminergic neuronal damage purportedly involves transport of newly released dopamine from extracellular spaces into 5-hydroxytryptaminergic terminals. This hypothesis is based primarily on findings that dopamine is required for, whereas 5-hydroxytryptamine (5-HT) uptake inhibitors prevent, methamphetamine-induced deficits in 5-hydroxytryptaminergic neuronal function. This hypothesis is not, however, supported by findings presented in this study that 5-hydroxytryptaminergic neuronal damage, induced by p-chloroamphetamine, does not decrease [3H]dopamine uptake into rat brain synaptosomes prepared from 5-HT-transporter-containing tissue. Moreover, despite having greater affinity for the 5-HT transporter, citalopram has an IC50 for [1H]dopamine transport into these synaptosomal preparations that is considerably greater than that of fluoxetine. These data suggest that 5-HT transporters may not effect dopamine uptake and thereby methamphetamine-induced 5-hydroxytryptaminergic neuronal damage. Other possible mechanisms related to 5-HT uptake inhibitor attenuation of methamphetamine-induced deficits were investigated. Fluoxetine pretreatment prevented the methamphetamine-induced decrease in tryptophan hydroxylase activity: this effect cannot be attributed to altered body temperatures or brain concentrations of methamphetamine which suggests that neither, per se, is sufficient to impair 5-hydroxytryptaminergic neuronal function.
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PMID:Methamphetamine-induced decrease in tryptophan hydroxylase activity: role of 5-hydroxytryptaminergic transporters. 914 69

A small group of neurons in the hypothalamic dorsomedial nucleus (DMN) have been reported to contain serotonin after pharmacological treatments enhancing brain serotonin levels. This study aimed at elucidating whether these neurons are able to synthesize serotonin de novo, and whether they possess a specific serotonin transport mechanism. Serotonin content in these neurons was raised by administration of L-tryptophan and pargyline. Double immunostaining for serotonin and tryptophan hydroxylase (TpOH), the serotonin synthesizing enzyme, revealed that none of the serotonin-containing neuronal somata expressed TpOH. Intracerebroventricular colchicine treatment did not result in TpOH-IR in these neurons. Fluoxetine, a specific serotonin transport inhibitor, prevented the accumulation of serotonin in these neurons. The present results thus indicate that the serotonin-containing DMN neurons are not able to synthesize serotonin. Instead, they take up exogenous serotonin via a specific serotonin transport mechanism. As serotonin and DMN are associated with various physiological functions, such as regulation of food intake and modulation of fear and anxiety, the mechanisms revealed in the present study may participate in these clinically important brain functions.
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PMID:Serotonin is not synthesized, but specifically transported in the neurons of the hypothalamic dorsomedial nucleus. 975 Nov 63

Using 1-ethyl-3(3-dimethyl-aminopropyl)-carbodiimide (EDAC) fixation and immunocytochemical confocal microscopic study, bright serotonin and histamine fluorescence appeared in the nucleus of rat peritoneal mast cells. In case of paraformaldehyde fixation, this was not observed. The phenomenon can be explained by the cross-linking effect of EDAC, which did not allow the efflux of biogenic amines from the nucleus. This means that biogenic amines are present in the nucleus of mast cells, and this is supported by the flow cytometric measurement data of the whole cell. Other hormones studied (triiodothyronine, insulin, and endorphin) were not present in the nucleus. Four pharmaca with biogenic amine-influencing character in the central nervous system were used for studying the relation between the external (surrounding and cytoplasmic) and nuclear biogenic amine content of mast cells. Fluoxetine, a serotonin reuptake inhibitor depleted nuclear as well as cytoplasmic serotonin content. Clorgyline, a MAO-A inhibitor, decreased cytoplasmic serotonin content and weakened nuclear serotonin fluorescence. The tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA), and the mast cell degranulator, Compound 48/80, reduced cytoplasmic serotonin content without influencing nuclear content. Histamine fluorescence was influenced solely by fluoxetine. The results show that nuclear 5-HT content is dependent firstly of serotonin uptake and reuptake. To our knowledge, this is the first exact report on the presence of non-steroid-type-receptor-transported hormones inside the nucleus of a cell.
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PMID:Hormones in the nucleus. Immunologically demonstrable biogenic amines (serotonin, histamine) in the nucleus of rat peritoneal mast cells. 1633 78

The effect of the tryptophan hydroxylase inhibitor, PCPA methylester, the serotonin reuptake inhibitor fluoxetine and MAO-A inhibitor clorgyline on the serotonin content of rat immune cells was studied, using labelled antibodies and flow cytometry. Each molecule significantly increased in males the serotonin concentration of peritoneal lymphocytes and the monocyte-macrophage-granulocyte group (mo-gran), however the agents were ineffective towards mast cells. In females fluoxetine and clorgyline increased the serotonin concentration in peritoneal lymphocytes and mo-gran. Fluoxetine also increased the serotonin level in mast cells. Thymus was absolutely resistant to the drugs in both genders. The results call attention (1) to the reverse effect of serotonin-acting agents on immune cells, (2) to the influence of the milieu where the cell is located and (3) the effect of gender.
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PMID:Effect of serotonin-acting agents on the serotonin content of immune cells. A peculiar observation. 1661 40

Selective serotonin (5-HT) reuptake inhibitors such as fluoxetine are widely used in the treatment of depression and anxiety; however, the mechanisms underlying their action and particularly the delay in therapeutic onset remain unclear. It is proposed that 5-HT reuptake inhibitors exert their therapeutic activity by increasing serotonergic neurotransmission; therefore, the aim of the present study was to investigate the effects of repeated treatment with fluoxetine (25 mg/kg/day p.o., 14 days) on expression of genes coding for proteins that involved in the synthesis and reuptake of 5-HT. Exposure of animals to plus-maze conditions on the first day of drug administration produced an increase in baseline anxiety on subsequent trial 2 weeks later. Fluoxetine strengthened the anxiogenic effects of maze experience. Two-week fluoxetine treatment also significantly reduced expression of tryptophan hydroxylase-2 (TPH2) and 5-HT transporter mRNAs as determined by RT-PCR in the brainstem. These changes were consistent with the decreased 5-HT levels and 5-HT turnover in the brain, and might contribute to the anxiogenic effects of the drug. The results also suggest that recently found association between treatment responses to fluoxetine and polymorphic variants of human TPH2 gene [Peters EJ, Slager SL, McGrath PJ, Knowles JA, Hamilton SP. Investigation of serotonin-related genes in antidepressant response. Mol Psychiatry 2004; 9:879-889] may be related to the drug effect on the TPH2 gene expression.
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PMID:Effect of repeated treatment with fluoxetine on tryptophan hydroxylase-2 gene expression in the rat brainstem. 1698 82

5,7-Dihydroxytryptamine (5,7-DHT), is an experimentally widely used selective serotonergic neurotoxin, though the mechanisms of toxicity remain to be fully elucidated. In the present study, we evaluated 5,7-dihydroxitryptamine (5,7-DHT) induced serotonergic neurotoxicity in foetal raphe serum free cultures from the rat. For this purpose, a model of foetal raphe serum free neuronal cultures from the rat was established, containing about 16% serotonergic neurons and studied up to 3 months. Two weeks old raphe cultures were exposed to the serotonergic neurotoxin 5,7-DHT (concentration range 10-100 microM) for 72 h, after which the medium was replaced and neurotoxicity was evaluated by immunocitochemistry 1 week later. Lactate dehydrogenase release into the medium, 72 h after exposure to 5,7-DHT, showed a concentration-dependent neurotoxicity. To access morphologically the serotonergic toxicity tryptophan hydroxylase (TPH) was used as a specific marker of these neurons. Immunocitochemistry using TPH antisera showed a concentration-dependent serotonergic neurotoxicity induced by 5,7-DHT. Serotonergic neurons showed the typical pattern of "pruning" accompanied by axon terminals and dendrites loss, which were either partial or total. The axotomy induced by the neurotoxin was morphologically characteristic of retrograde axonal degeneration. Fluoxetine (0.1 microM) pre-treatment reduced 5,7-DHT-induced serotonergic neurotoxicity. These results indicate that the mechanism by which 5,7-DHT-induces serotonergic neurotoxicity is, at least partially, dependent on the toxin uptake by the serotonin transporter. Finally, we have established a robust model of primary raphe neuronal culture to evaluate serotonergic neurons development and the mechanisms of toxicity involving this neuronal population.
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PMID:5,7-Dihydroxitryptamine toxicity to serotonergic neurons in serum free raphe cultures. 1851 35

During the same postnatal period of development when their terminal projection patterns in the midbrain are maturing, lateral superior olivary (LSO) neurons are immunoreactive for serotonin (5-HT). As there is no evidence that LSO neurons synthesize 5-HT, it is likely that they accumulate 5-HT via the 5-HT transporter. To determine if the 5-HT transporter is responsible for 5-HT inside postnatal mouse LSO neurons, pups (postnatal ages 5-6) were treated with fluoxetine and LSO neurons examined for 5-HT. We also evaluated whether LSO neurons containing 5-HT expressed the 5-HT transporter. To further rule out any potential synthesis of 5-HT, brainstem sections of mice at postnatal ages when 5-HT staining is the most robust were stained for the rate-limiting enzyme in the synthesis of 5-HT, tryptophan hydroxylase. Fluoxetine treatment reduced or in most cases, completely eliminated the number of neurons in the LSO stained for 5-HT. Postnatal LSO neurons containing 5-HT were immunoreactive for the 5-HT transporter; in older animals in which 5-HT was no longer observed in the LSO neurons, 5-HT transporter expression was similarly absent. Further, LSO neurons in mice at any age did not stain for tryptophan hydroxylase. These results indicate that LSO neurons express the functional 5-HT transporter to internalize 5-HT; this mechanism may serve to regulate extracellular 5-HT levels during maturation of their terminal endings in the inferior colliculus.
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PMID:Experimental evidence that the serotonin transporter mediates serotonin accumulation in LSO neurons of the postnatal mouse. 1907 Jun 5


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