Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet 5-hydroxytryptamine (5-HT) uptake was measured in asymptomatic headache patients attending a specialist migraine clinic, and in hospital staff who did not suffer from regular or severe headache. Current levels of anxiety and depression were assessed in all subjects using the Hospital Anxiety and Depression (HAD) scale and their possible influence on the uptake kinetics taken into account during the analysis of results. The Michaelis-Menten constant (Km) was significantly raised in common migraine and tension headache compared with controls (p less than 0.001 and p less than 0.01, respectively), but not in classical migraine or cluster headache. The increase remained significant after adjusting for differences in age, sex, presence of anxiety or depression (HAD sub-scale score greater than or equal to 8), drug intake during the week before testing, time elapsed since last attack and time of assay (am or pm). No differences were observed between patients and controls in the maximal rate of uptake (Vmax) or platelet count, and previous reports of a reduction in Vmax in patients experiencing attack within 5 days prior to testing could not be confirmed. The cause and significance of an increased Km are not clear, but plasma factors acting as competitive inhibitors for the uptake site or an alteration in the configuration of the uptake site are possible explanations. If confirmed, the shared biochemical abnormality may suggest that common migraine and tension headache have a common pathogenesis.
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PMID:Kinetics of platelet 5-hydroxytryptamine uptake in headache patients. 188 70

Selective antagonism of serotonin (5-hydroxytryptamine, 5HT) and noradrenaline transport by antidepressants is a key element in the 'amine' hypothesis of affective disorders. Uptake and/or transport sites of 5HT have been reported to be reduced in platelets of patients suffering from depression and in post-mortem brain samples of depressed patients and suicide victims. To date there has been little molecular information available on the structure and regulation of 5HT transporters. Using the polymerase chain reaction with degenerate oligonucleotides derived from two highly conserved regions of the transporters for noradrenaline and gamma-aminobutyric acid (GABA), we have identified a large family of related gene products expressed in rodent brain. One of these products hybridizes to a single 3.7-kilobase RNA restricted to rat midbrain and brainstem, where it is highly enriched within the serotonergic raphe complex. Transfection with a single 2.3-kilobase brainstem complementary DNA clone is sufficient to confer expression of a Na(+)-dependent 5HT transporter upon nonneural cells, with transport selectively and potently antagonized by 5HT uptake-specific antidepressants, including paroxetine, citalopram and fluoxetine.
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PMID:Cloning and expression of a functional serotonin transporter from rat brain. 194 72

Gepirone is a serotonin (5-hydroxytryptamine, 5-HT) type1A receptor agonist and a pharmacologic analogue of buspirone. Two double-blind, placebo-controlled studies show the efficacy of gepirone in the treatment of major depression. Study 1 demonstrates gepirone's superiority over placebo in an 8-week acute treatment of patients with major depression, including the melancholic subtype. Gepirone's antidepressant dose range is tentatively established at 5-30 mg/day. Study 2 reveals the benefit of gepirone compared with placebo in 4-week continuation therapy of patients with major depression who initially responded to 6 weeks of open therapy with gepirone. Analysis of Hamilton Rating Scale for Depression item scores show gepirone especially improves scores on items of core depression.
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PMID:Gepirone in the treatment of major depression. 197 42

The response of guinea pig trachea to 5-hydroxytryptamine (serotonin; 5-HT) was investigated by studying tracheal strips suspended in organ chambers for isometric tension measurements. Serotonin concentrations of 0.1 to 10 microM produced concentration-dependent contractions, whereas at higher concentrations (10-300 microM) the agonist caused concentration-dependent relaxations. The 5-HT2 antagonist ketanserin shifted the bimodal 5-HT response-curve to the right (pA2 for ketanserin was 8.98). The 5-HT1A agonist, (+)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide and 5-HT3 antagonist, ICS 205930 (3-tropanyl-indole-3-carboxylate) had no effect on the 5-HT-response curve. Incubation with atropine resulted in a depression of the maximal contractility and an increase in the EC50 without changing the bimodal nature of the concentration-response curve. Hexamethonium was able to block the atropine effect without significantly affecting the 5-HT concentration-response curve. Neither the constriction nor the relaxation was altered by propranolol, chlorpheniramine or capsaicin pretreatment. Histamine and carbachol preconstricted airways were also relaxed by 5-HT in a concentration-dependent fashion and this relaxation was antagonized by ketanserin (pKb for ketanserin in histamine preconstricted airways was 9.4). Epithelial denudation did not inhibit the 5-HT-induced relaxation. 5-HT stimulated inositol-monophosphate production which also exhibited a bimodal response and correlated well with the functional response. The above findings suggest that 5-HT causes both constriction and relaxation of the guinea pig airway, and that both responses are antagonized by a 5-HT2 receptor blocker. In addition, part of the constrictor response of 5-HT is mediated through a cholinergic preganglionic pathway. Finally, inositol-monophosphate production induced by 5-HT correlates with the functional response.
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PMID:Serotonin induces constriction and relaxation of the guinea pig airway. 197 97

The effects of prostaglandin F2 alpha, prostaglandin E1, prostaglandin E2 and the thromboxane A2 analogue U46619 were determined in ring segments of human hand veins. All prostanoids except prostaglandin E1 elicited contraction. The order of potency was U46619 greater than prostaglandin F2 alpha greater than prostaglandin E2. The thromboxane receptor antagonists BM13,505 and AH23848 both caused a parallel rightward displacement of the concentration-response curve for U46619 without depression of the maximum contraction, suggesting competitive antagonism. Schild plots for both antagonists yielded regression lines with slope indices not significantly different from unity. The pA2 values for BM13,505 and AH23848 were 7.9 and 8.4 respectively. Both antagonists also effectively inhibited prostaglandin F2 alpha-induced contractions. However, AH23848 significantly reduced the maximum response, and the results with BM13,505 gave no clear indication of the type of inhibition. In vein segments submaximally contracted by 5-hydroxytryptamine, prostaglandins E1 and E2 produced a biphasic response with a relaxation at low and a contraction at high concentrations. Prostaglandin F2 alpha and U46619 failed to elicit relaxation under these conditions. However, in the presence of either thromboxane receptor antagonist, prostaglandin F2 alpha but not U46619 produced a relaxation. The results are compatible with the presence of at least two prostanoid receptors in human hand veins, a contraction-mediating thromboxane receptor and an as yet unclassified receptor eliciting relaxation. U46619 was a potent agonist at the thromboxane receptor and prostaglandin E1 and E2 preferentially stimulated the relaxation-mediating receptor, whereas prostaglandin F2 alpha appeared to be active at both receptor sites.
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PMID:Characterization of contraction-mediating prostanoid receptors in human hand veins: effects of the thromboxane receptor antagonists BM13,505 and AH23848. 205 48

Cocaine potently inhibits the spontaneous activity of dorsal raphe serotonin (5-hydroxytryptamine [5-HT] neurons which possess impulse-modulating receptors of the 5-HT1A subtype. In an investigation of the neuropharmacologic mechanisms underlying this electrophysiologic effect, we have compared cocaine with structurally and functionally similar compounds, attempted to reverse cocaine-induced suppression of 5-HT dorsal raphe nucleus (DRN) neuronal activity, and assessed the effects of 5-HT depletion on the response to cocaine. Extracellular recordings in chloral hydrate-anesthetized rats were obtained using single-unit recording techniques; drugs were infused intravenously IV) in a cumulative dose manner. The active isomer (-)-cocaine (ID50 = 0.5 +/- 0.15 mg/kg) and the phenyltropane analogue WIN 35428 (ID50 = 0.17 +/- 0.03 mg/kg) that share the ability of cocaine to block monoamine uptake also inhibit impulse activity in 5-HT neurons. In contrast, the inactive isomers (+)-cocaine, (+)-pseudococaine and the metabolite benzoylecgonine do not exhibit the same range of potency (maximal 20% to 30% inhibition at a cumulative dose of 8 to 16 mg/kg). A selective inhibitor of uptake for 5-HT (fluoxetine; ID50 = 1.8 +/- 0.5 mg/kg), but not norepinephrine (desipramine) or dopamine (GBR 12909), mimicked cocaine, as did the monoamine releaser amphetamine (ID50 = 2.86 +/- 0.46 mg/kg). The putative 5-HT1A autoreceptor antagonist spiperone reversed the cocaine-induced depression of firing rate in 64% of 5-HT neurons tested whereas receptor antagonists for dopamine D2 (haloperidol), 5-HT2 (ketanserin), gamma-aminobutyric acid (picrotoxin) and 5-HT1/beta-adrenergic (propranolol) were ineffective. Following treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (100 mg/kg/day of the base for 3 days), impulse depression induced by cocaine was significantly attenuated as compared to control, which suggests that the effects of cocaine may be dependent on endogenous 5-HT stores. In summary, these findings support the hypothesis that the inhibitory effects of cocaine on 5-HT DRN neurons are mediated by increased 5-HT available for interaction with 5-HT1A impulse-regulating autoreceptors in the DRN, as a consequence of cocaine-induced blockade of 5-HT reuptake processes. Further studies are required to clarify the relative contribution of cocaine-5-HT interactions to the behavioral and physiologic effects of this psychostimulant.
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PMID:The interaction of cocaine with serotonin dorsal raphe neurons. Single-unit extracellular recording studies. 213 98

L-5-Hydroxytryptophan (5HTP) was administered to 20 patients suffering from panic disorder and to 20 healthy controls. Subjects received 60 mg 5HTP in 300 ml saline solution. Before, during, and up to 2 hours after 5HTP administration, symptoms of anxiety and depression were assessed. In addition, plasma 5HTP, 3-methoxy-4-hydroxyethylglycol (MHPG), cortisol, beta-endorphin, and melatonin levels were measured at several time points, and the kinetics of 5-hydroxytryptamine (5HT) in blood platelets were measured. During and after the infusion of 5HTP, none of the patients showed an increase in anxiety or depressive symptoms, despite the presence of severe side effects. Some patients even experienced the 5HTP infusion as a relief. In contrast to the patients, nine control subjects reported depressed mood, although no increases in anxiety were noted. In both patients and controls, the 5HTP infusion led to substantial increases in plasma cortisol and beta-endorphin levels, while the plasma MHPG level was unchanged. Plasma melatonin increased significantly after 5HTP administration, suggesting that increasing 5HT availability in man might affect melatonin synthesis. The results of this study are at odds with the hypothesis that there is a supersensitivity of 5HT2 receptors in panic disorder.
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PMID:Behavioral, neuroendocrine, and biochemical effects of 5-hydroxytryptophan administration in panic disorder. 213 31

The pathophysiology of acute lung injury after long bone fracture may be associated with endothelial damage and altered fibrinolysis. Accordingly, we studied metabolic functions of pulmonary endothelial cells: 5-hydroxytryptamine (5-HT) uptake and angiotensin-converting enzyme (ACE) activity in anesthetized rabbits before and every 4 h after long bone fracture (n = 12) or sham (n = 6). To assess changes in fibrinolysis, we studied levels of plasminogen activator inhibitor (PAI), an inhibitor of the fibrinolytic cascade. All animals in the control group and only 6 of 12 animals in the long bone fracture group survived 12 h. 5-HT uptake was depressed after 8 h in both groups. By 12 h, however, 5-HT uptake in the long bone fracture group remained depressed, but returned to baseline in the control group. Conversely, ACE activity was unchanged in both groups. PAI levels were increased in both groups at 4 h. During the next 8 h, levels in the long bone fracture group continued to increase and remained elevated, whereas levels in the control group decreased and were not greater than baseline at 12 h. Initial PAI and 5-HT uptake changes may be related to surgical preparation of the rabbit. Prolonged depression of 5-HT uptake suggests that musculoskeletal trauma is associated with pulmonary endothelial damage. Finally, impaired fibrinolysis due to increased PAI may contribute to the pathogenesis of endothelial injury after long bone fracture.
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PMID:Pulmonary endothelial injury and altered fibrinolysis after femur fracture in rabbits. 217 94

The azapirone class of anxiolytic drugs is being evaluated for clinical use in the treatment of depression. Buspirone, a serotonin (5-hydroxytryptamine, 5-HT) partial agonist active at the 5-HT1A receptor subtype, was evaluated in the treatment of depression in a series of five placebo-controlled, parallel group studies involving 382 patients with DSM-III major depression and significant associated anxiety symptoms (both Hamilton depression [HAM-D] and Hamilton anxiety [HAM-A] scales greater than or equal to 18). Buspirone therapy was initiated at 15 mg/day with individual dose titration to a maximum of 90 mg/day and resulted in marked improvement in both depressive and anxiety symptoms. Analyses of the composite data base from the five studies show significant (p less than 0.05) improvement in mean HAM-D, HAM-A, and Clinical Global Impression-Global Improvement scale ratings for buspirone-treated compared with placebo-treated patients. Of particular interest was significant improvement in cardinal depression symptoms, e.g., depressed mood, guilt, work and interest, anergia, and diurnal variation of mood. Subset analyses revealed that patients with melancholic-type major depression and patients with more severe symptoms (judged by higher initial HAM-D or HAM-A total scores) responded better to buspirone than did patients who were less ill. The buspirone dose most frequently associated with clinically significant improvement was 40 mg/day. Gepirone, an analogue of buspirone with highly selective binding affinity for the 5-HT1A receptor subtype, also shows promise of antidepressant efficacy in preliminary controlled clinical trials. These data suggest that azapirones, which as partial agonists modulate 5-HT1A receptor function, have clinically important antidepressant properties.
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PMID:Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression. 219 3

Clomipramine, a preferential inhibitor of 5-hydroxytryptamine uptake, has proven effective in the management of depression, resistant depression, and obsessive compulsive disorder. Investigators have also reported benefits of this medication in patients with phobia, panic disorder, chronic pain, Gilles de la Tourette's syndrome, premature ejaculation, anorexia nervosa, cataplexy, and enuresis. In double-blind studies of patients with depression, clomipramine has been significantly more effective than placebo and equivalent to standard tricyclics. Clomipramine is particularly well suited for the treatment of resistant depression, for which its efficacy may be enhanced by combination therapy with tryptophan and/or lithium. In at least 12 double-blind comparative trials, clomipramine has exhibited significant benefit in patients with obsessive compulsive disorder, this efficacy not being limited to patients with an associated depressive illness. In the United States, clomipramine is approved only for the treatment of obsessive compulsive disorder.
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PMID:Worldwide use of clomipramine. 219 35


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