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)

This study examined, in the largest sample of major depressives reported so far, platelet serotonergic parameters (5-HT uptake, [3H]paroxetine binding and 5-HT2A receptors measured by [3H]LSD binding) in 60 antidepressant-free depressed patients and 40 age- and gender-matched control subjects before treatment, and in 45 major depression patients during treatment with antidepressants. We found that, at baseline, the density (Bmax) of 5-HT2A receptors was significantly higher (by 39%) in depressed patients than in controls. Suicidal patients had significantly higher Bmax values than controls or non-suicidal patients. The rate of serotonin uptake (Vmax), but not the uptake at a single concentration, was significantly higher in depressed patients, particularly in females. There was no significant difference between the Kd or Bmax of [3H]paroxetine binding in control and depressed subjects. Treatment with antidepressant drugs of different pharmacological profile had no significant effect on the density of 5-HT2A receptors, nor did the receptor number predict the response to treatment. The affinity of serotonin uptake site for 5-HT and [3H]paroxetine significantly decreased during treatment with antidepressants, particularly SSRIs. Suppression of 5-HT uptake correlated with decreases in Hamilton depression (HAMD) scores. Our data suggest that the increased density of platelet 5-HT2A receptors may be associated with untreated major depression in antidepressant-free depressed patients, in particular those with suicidal thoughts. The persistence after antidepressant treatment and clinical improvement would suggest that up-regulation of 5-HT2A receptors is a trait rather than state phenomenon. Correlation of 5-HT uptake suppression with decreases in HAMD scores suggests that serotonin uptake inhibition is a relevant factor in antidepressant drug effect and clinical improvement.
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PMID:Platelet serotonergic indices in major depression: up-regulation of 5-HT2A receptors unchanged by antidepressant treatment. 907 72

The role of 5-HT2 receptors in nociceptive behaviour of rats was investigated using spinal administration of the 5-HT2A/2C receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI), the 5-HT2A/2C antagonist ketanserin and the glutamate receptor agonist NMDA. Nociceptive behaviour was scored after injections at upper thoracic or lumbosacral levels. DOI (0.1-10 mM, 15 microl) administered at the upper thoracic level induced pain-like behaviour in a dose-dependent manner and a long-lasting motor depression at the greatest dose. At the lumbosacral level a similar dose-dependent pain-like behaviour was observed, but it was less pronounced. Motor depression was not observed at any dose. Ketanserin injected before DOI blocked both nociceptive and motor effects. Stimulation of both NMDA and 5-HT2A/2C receptors had a mutually potentiating effect. The present results show that the effects of DOI were more pronounced at the upper thoracic than at the lumbosacral level. This is possibly caused by the difference in 5-HT2A/2C receptor density at the two levels. The motor depression induced by the greatest dose of DOI given at the upper thoracic level appears to mask the pain-like behaviour. The nociceptive behaviour seen after DOI injection is further increased following co-injection of NMDA.
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PMID:Differential effects of activation of lumbar and thoracic 5-HT2A/2C receptors on nociception in rats. 907 92

Nefazodone hydrochloride is a phenylpiperazine antidepressant with a mechanism of action that is distinct from those of other currently available drugs. It potently and selectively blocks postsynaptic serotonin (5-hydroxytryptamine; 5-HT) 5-HT2A receptors and moderately inhibits serotonin and noradrenaline (norepinephrine) reuptake. In short term clinical trials of 6 or 8 weeks' duration, nefazodone produced clinical improvements that were significantly greater than those with placebo and similar to those achieved with imipramine, and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine and sertraline. The optimum therapeutic dosage of nefazodone appears to be between 300 and 600 mg/day. Limited long term data suggest that nefazodone is effective in preventing relapse of depression in patients treated for up to 1 year. Analyses of pooled clinical trial results indicate that nefazodone and imipramine produces similar and significant improvements on anxiety- and agitation-related rating scales compared with placebo in patients with major depression. Short term tolerability data indicate that nefazodone has a lower incidence of adverse anticholinergic, antihistaminergic and adrenergic effects than imipramine. Compared with SSRIs, nefazodone causes fewer activating symptoms, adverse gastrointestinal effects (nausea, diarrhoea, anorexia) and adverse effects on sexual function, but is associated with more dizziness, dry mouth, constipation, visual disturbances and confusion. Available data also suggest that nefazodone is not associated with abnormal weight gain, seizures, priapism or significant sleep disruption, and appears to be relatively safe in overdosage. Nefazodone inhibits the cytochrome P450 3A4 isoenzyme and thus has the potential to interact with a number of drugs. Further long term and comparative studies will provide a more accurate assessment of the relative place of nefazodone in the management of major depression. Nonetheless, available data suggest that nefazodone is a worthwhile treatment alternative to tricyclic antidepressants and SSRIs in patients with major depression.
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PMID:Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression. 921 Oct 88

The aim of the present study was to determine the effect of estradiol-17 beta (E2), in its positive feedback mode for gonadotropin release, on the serotonin transporter (SERT) in female rat brain. Levels of SERT mRNA were determined by in situ hybridization and SERT-binding sites were measured by quantitative [3H]paroxetine receptor autoradiography. The injection of estradiol benzoate (EB) in acutely ovariectomized rats increased significantly (approximately 50%) the numbers of cells that expressed SERT mRNA in the dorsal raphe nucleus and the density of SERT-binding sites in lateral septum (90%), basolateral amygdala (20%), ventral nucleus of thalamus (250%) and ventromedial hypothalamic nucleus (250%). SERT-binding sites in EB-treated rats were significantly lower in periaqueductal central grey (15%). These findings indicate that effects on SERT gene expression may be involved in the E2-induction of the gonadotropin surge. Together with our previous findings, they also suggest that the sex differences in depression and the apparent psychotropic effect of E2 may be due to the action of E2 on the serotonin transporter as well as 5-HT2A receptors.
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PMID:Estradiol-17 beta increases serotonin transporter (SERT) mRNA levels and the density of SERT-binding sites in female rat brain. 910 66

Abnormal interactions between serotonin (5-hydroxytryptamine) and glucocorticoids, notably in the hippocampus, may underpin neuroendocrine, affective and cognitive dysfunction in depression and ageing. Glucocorticoids act via intracellular glucocorticoid and mineralocorticoid receptors, whereas 5-hydroxytryptamine binds to a family of transmembrane sites; both cross- and auto-regulation have been proposed. To determine the roles of 5-hydroxytryptamine and corticosterone in the short-term control of hippocampal receptor gene expression, we used 3,4-methylenedioxymethamphetamine (20 mg/kg), which causes acute release of both 5-hydroxytryptamine and corticosterone. 3,4-methylenedioxymethamphetamine increased mineralocorticoid receptor messenger RNA expression throughout the hippocampus after 16 h. In rats with fixed glucocorticoid levels (adrenalectomy plus corticosterone pellets) this effect was lost in CA1-4, suggesting corticosterone-mediation, but maintained in the dentate gyrus, indicating 5-hydroxytryptamine involvement. In contrast, 3,4-methylenedioxymethamphetamine decreased glucocorticoid receptor messenger RNA expression in the dentate gyrus and CA1 within 4 h, but only in adrenal-intact rats, suggesting corticosterone control. 5-Hydroxytryptamine1A receptor messenger RNA expression was decreased in CA1 in both groups of rats, but increased in the dentate gyrus only in corticosterone-fixed rats, suggesting 5-hydroxytryptamine differentially regulates expression of this gene within hippocampal subfields. 5-hydroxytryptamine2C receptor messenger RNA was decreased in ventral CA1 only in adrenal-intact rats, suggesting a corticosterone effect, and decreased in the subiculum in both groups, indicating 5-hydroxytryptamine mediation. These results show the complexity and intricate subregional-specificity of 5-hydroxytryptamine and corticosterone interactions upon hippocampal corticosteroid and 5-hydroxytryptamine receptor gene expression. 3,4-Methylenedioxymethamphetamine-induced alterations in hippocampal receptor gene expression may play a role in the mood and behavioural changes associated with this drug of abuse.
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PMID:Site-specific regulation of corticosteroid and serotonin receptor subtype gene expression in the rat hippocampus following 3,4-methylenedioxymethamphetamine: role of corticosterone and serotonin. 913 93

We have previously shown that risperidone, an antipsychotic drug with high affinity for 5-hydroxytryptamine (5-HT)2A and dopamine (DA)2 receptors, as well as for alpha 2- and alpha 2-adrenoceptors, enhances 5-HT metabolism selectively in the rat frontal cortex (FC). To further study the influence of risperidone on central 5-HT systems, we compared its effects on dialysate 5-HT in the FC, as assessed by microdialysis, with those obtained with other antipsychotic drugs, i.e., clozapine, haloperidol, and amperozide, as well as with the selective alpha 2- or 5-HT2A receptor antagonists idazoxan or MDL 100,907, respectively. The underlying mechanism for risperidone's effect on 5-HT output in the FC was also investigated using single-cell recording in the dorsal raphe nucleus (DRN). Administration of risperidone (0.2, 0.6, and 2.0 mg/kg, SC) dose-dependently increased 5-HT levels in the FC. This stimulatory action was mimicked by amperozide (10 mg/kg, SC) and, to some extent, by idazoxan (0.25 mg/kg, SC). In contrast, clozapine (10 mg/kg, SC), haloperidol (2.0 mg/kg, SC), and MDL 100,907 (1.0 mg/kg, SC) exerted only minor effects on 5-HT output in brain. Local administration of risperidone or idazoxan (1.0-1000 mumol/L) in the FC dose-dependently increased dialysate levels of 5-HT in this region. On the other hand, risperidone 25-800 micrograms/kg, IV) dose-dependently decreased the firing rate of 5-HT cells in the DRN, an effect that was largely antagonized by pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms/kg, IV). These results indicate that the risperidone-increased 5-HT output in the FC may be related to its alpha 2-adrenoceptor antagonistic action, a property shared with both amperozide and idazoxan, and that this action probably is executed at the nerve terminal level. The inhibition of 5-HT cell firing by risperidone is probably secondary to increased 5-HT availability, e.g., in the DRN, since it could be antagonized by a 5-HT1A receptor antagonist. The enhanced 5-HT output in the FC by risperidone may be of particular relevance for the treatment of schizophrenia when associated with depression and in schizoaffective disorder.
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PMID:Risperidone dose-dependently increases extracellular concentrations of serotonin in the rat frontal cortex: role of alpha 2-adrenoceptor antagonism. 919 49

Depression is a significant problem in the elderly. Because of aging-related pharmacokinetic and pharmacodynamic changes, it is not possible to automatically extrapolate findings on the efficacy or tolerability of antidepressants from younger to older populations. Venlafaxine inhibits both noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake. Analysis of data from phase II and III trials showed that venlafaxine was comparably effective in the young and in a subset of over 350 elderly patients. Venlafaxine dosage needs to be lowered in the elderly with renal impairment. As a weak cytochrome P450 (CYP) inhibitor, it is unlikely to have clinically significant drug interactions. Venlafaxine may be associated with some increase in supine diastolic blood pressure, especially at dosages above 150 mg/day. Nefazodone is a serotonin uptake inhibitor and serotonin 5-HT2A receptor antagonist. Pooled analysis of about 250 patients found nefazodone to be effective in elderly individuals with moderate or severe depressive symptoms, with or without melancholia, in both primary and recurrent episodes. Nefazodone clearance is reduced in patients with hepatic impairment, and plasma concentrations have been reported to be higher in the elderly. Nefazodone is an inhibitor of the CYP3A4 family. There does not appear to be any increase in the frequency or severity of adverse effects in the elderly. Moclobemide is a selective inhibitor of monoamine oxidase type A. Studies in the elderly have found it to be well tolerated and meta-analysis has shown it to be comparably effective in young and elderly populations, and comparable to other antidepressants in terms of efficacy. Neither age nor renal impairment necessitate dosage adjustment, but hepatic impairment does necessitate dosage reduction. Dietary restrictions are not required. Overall, there is a relative paucity of data on the tolerability and efficacy of newer antidepressants in the elderly, especially those with concomitant medical disorders. Data that are available indicate that venlafaxine, nefazodone and moclobemide have comparable efficacy in older and younger patients.
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PMID:Antidepressant use in the elderly. Current status of nefazodone, venlafaxine and moclobemide. 925 75

In vitro experiments were conducted on neonatal rat brainstem-spinal cord preparations to test the hypothesis of an inhibitory modulation of phrenic activity by serotonin (5-HT) via non-5-HT2A receptors [Lindsay, A.D. and Feldman, J.L., Modulation of respiratory activity of neonatal rat phrenic motoneurones by serotonin, J. Physiol., 461 (1993) 213-233]. The changes induced by 5-HT and related agents on phrenic root discharges and membrane currents in identified phrenic motoneurons were analysed after blockade of spinal 5-HT2A receptors. Spinal application of 5-HT1B (but not 5-HT1A) receptor agonists depressed the phrenic activity and the effect was prevented by pretreatment with 5-HT1B (but not 5-HT1A, 5-HT2A and 5-HT3) receptor antagonists. Results from phrenic motoneuron whole cell recordings do not reject a presynaptic location of the 5-HT receptors responsible for this depression.
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PMID:Serotonergic inhibition of phrenic motoneuron activity: an in vitro study in neonatal rat. 925 56

The effects of chronic corticosterone treatment (100 mg pellet implanted for 1 week) were assessed in animal tests of anxiety, exploration and motor activity, and changes in binding to 5-HT1A and 5-HT2A receptors, and the 5-HT transporter, were measured. At the end of the week's treatment, the corticosterone concentration was significantly elevated and there were significant decreases in adrenal, thymus and body weights. However, there were no changes in the measures of anxiety in the social interaction test or on trials 1 and 2 of the elevated plus-maze. Also supporting a dissociation between anxiety and elevated corticosterone concentrations are previous findings that benzodiazepine withdrawal causes increased anxiety but no change in corticosteroid concentrations. Therefore these two situations provide a double dissociation between anxiety and elevated corticosteroids. Decreased 5-HT1A receptor binding in the dentate gyrus and increased 5-HT2A receptor binding in the parietal cortex was found following chronic corticosterone treatment. This reciprocal relationship between 5-HT1A and 5-HT2A receptors has been proposed to be important in mediating depression. The significant decreases in motor activity observed in all the test situations would be compatible with this proposal. Thus the constellation of behavioural and biochemical changes detected after chronic corticosterone treatment is more pertinent to depression than anxiety. One week after removal of the pellets, the behavioural and neurochemical changes had disappeared and the only differences to remain were decreased adrenal, thymus and body weights in the animals that had been treated chronically with corticosterone.
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PMID:Decreased 5-HT1A and increased 5-HT2A receptor binding after chronic corticosterone associated with a behavioural indication of depression but not anxiety. 937 82

The 5-hydroxytryptamine (5-HT) receptor(s) that mediate(s) contraction of the rat ileum longitudinal muscle was studied. 5-HT and alpha-methyl-5-HT equipotently induced contractions, whereas 5-methoxytryptamine and 2-methyl-5-HT (partial agonist) were less potent; this rank order of potency suggests involvement of a 5-HT2 receptor. Neither tetrodotoxin nor atropine affected the contraction to 5-HT, suggesting a smooth muscle localization of these 5-HT2 receptors. The presence of either a selective 5-HT2B (SB 204741), 5-HT3 (granisetron) or 5-HT4 (SB 204070) antagonist, slightly affected the contractions to 5-HT. Thus, they were also included in the organ bath solution in all subsequent experiments in order to pharmacologically isolate the main contractile component. Using (if possible) 5-HT2A receptor-selective concentrations, ketanserin, ritanserin, metergoline, spiperone, mianserin, methiothepin, mesulergine, methysergide and cisapride all inhibited the contractions to 5-HT, causing a depression of the curve to 5-HT (i.e. surmountable antagonism was not observed with any of the above agents). Comparison of the affinities of these compounds for the various 5-HT2 receptor subtypes revealed that the receptor involved in the contractions to 5-HT most closely resembles the 5-HT2A receptor. However, cinanserin at a concentration expected to inhibit 5-HT2A receptor-mediated effects, failed to affect the contractions to 5-HT. It is thus concluded that on the longitudinal smooth muscle of the rat ileum, at least a part of the contraction to 5-HT is mediated by 5-HT receptors resembling the 5-HT2A receptor subtype.
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PMID:5-HT receptor types in the rat ileum longitudinal muscle: focus on 5-HT2 receptors mediating contraction. 943 Jul 91


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