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)

1. The classical norepinephrine (NE) and serotonin (5-HT) theories of depression have been abandoned in light of recent chronic antidepressant drug studies. 2. The new NE and 5-HT theories of depression focus on the dynamics of receptor subtypes in depression and chronic antidepressant treatments. 3. Recent studies in molecular genetics suggest a reclassification of monoamine receptors based on receptor structural homologies in DNA and amino acid sequences rather than receptor affinity for ligands. 4. Electrophysiologic studies in rats suggest that 5-HT1 receptor function is facilitated by chronic antidepressant treatment. 5. Preclinical studies employing a range of 5-HT1 mediated behavioral models also suggest that chronic antidepressant treatment facilitates transmission at central 5-HT1 receptors. 6. Patient studies, employing a 5-HT1 mediated neuroendocrine model, suggest that depression is associated with decreased transmission at CNS 5-HT1 receptors; and that chronic antidepressant treatment facilitates 5-HT1 receptor responsiveness in depressed patients. 7. New 5-HT1 selective agonists have been developed and found to be clinically effective antidepressants. 8. The above clinical and preclinical data suggest that some forms of depression are related to a decreased responsiveness of 5-HT1 receptors which is reversed by chronic antidepressant treatment. 9. Beta adrenergic and NE-stimulated cyclic AMP studies suggest that chronic antidepressant treatment decreases the responsiveness of central beta-adrenergic receptors, particularly beta-1 receptors. 10. A novel approach to antidepressant drug development focuses on identifying centrally active beta-1 agonists, which like clinically proven antidepressants, decrease beta-1 receptor responsiveness with chronic treatment. 11. 5-HT2 receptor binding studies and initial studies of 5-HT2 receptor coupled PI turnover suggest that chronic antidepressant treatment decreases 5-HT2 receptor number and function. 12. The development of new atypical antidepressants with 5-HT2 receptor related mechanisms of action suggest that 5-HT2 receptors may be associated with certain types of depression and their clinical treatment.
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PMID:Depression and antidepressant therapy: receptor dynamics. 217 22

In search of a physiological marker of depression and suicidal behavior, serotonin receptors of the 5-HT2 type were studied on platelet membranes from 19 control and 22 suicidal subjects. All were young, drug- and medication free men (18-21-years-old). 5-HT2 receptor binding was assayed using tritiated ketanserin at two concentrations. Receptor binding in the suicidal subjects was significantly higher than controls at both concentrations, the mean difference being around 50%. A similar difference between patients with major depressive disorder and matched controls has been observed previously. These findings support the use of 5-HT2 receptors on platelets as a research and diagnostic tool in depression and suicide.
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PMID:Increased serotonin 5-HT2 receptor binding on blood platelets of suicidal men. 230 6

Serotonin receptors of the 5-HT2 type were studied on platelet membranes from 15 patients suffering from major depression. Receptor binding and clinical state (assessed by the Hamilton and Beck rating scales) were examined in a drug free state upon admission and after 1 and 3 weeks of treatment with the antidepressant maprotiline (MPT). 5-HT2 receptor binding changed in correlation with changes in the clinical state of the patients as judged by the rating scales. Since most patients showed a clinical improvement, the patients as a group exhibited a significant decrease in binding concomitant with a drop in depression scores. However, in those patients in whom there was no clinical change or an increase in depression scores, 5-HT2 receptor binding did not change or increased, respectively, thus resulting in a significant correlation between clinical changes and changes in binding. These results support the use of 5-HT2 receptors on platelets in evaluating depression and its treatment.
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PMID:Serotonin 5-HT2 receptor binding on blood platelets as a state dependent marker in major affective disorder. 239 11

The mode of interaction of some alpha-adrenoceptor ligands with the 5-HT2-receptor system was investigated in the calf coronary artery. Isometric contractions caused by 5-hydroxytryptamine (5-HT) were studied on strips without endothelium. Phentolamine antagonized competitively (pKB = 7.4) the effects of 5-HT. Phentolamine also prevented the methysergide-induced depression of contractions elicited by 5-HT. The alpha 1-selective ligand 127I-HEAT depressed the responses to 5-HT. Both phentolamine and ketanserin prevented the depressant effects of I-HEAT on 5-HT-induced contractions. These and previous experiments are consistent with the existence of the 5-HT2 receptor in two interconvertible states R in equilibrium with R'. Interconversions between the high affinity state R and low affinity state R' (for 5-HT) appear to be modulated by an allosteric site A. The present and previous data suggest four possible modes of interaction of alpha-adrenoceptor ligands with the 5-HT2-receptor system: (a) ligands that compete with 5-HT for the 5-HT2 receptor in the R state (examples are nonselective phentolamine, alpha 1-selective ketanserin and corynanthine, and alpha 2-selective yohimbine and rauwolscine); (b) ligands such as I-HEAT that through binding to A depress the response to 5-HT by favouring the R' state; (c) ligands, such as ketanserin and phentolamine, that through binding to A favour the R state; and (d) ligands, such as phenoxybenzamine, that cause a covalent modification of the R state but not of the R' state. Qualitative and quantitative considerations suggest that in the calf coronary artery the described features are unrelated to alpha 1- and alpha 2-adrenoceptors.
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PMID:A two-state model for the 5-HT2 receptor: effects of alpha-adrenoceptor ligands. 245 22

The effects of the novel, highly selective serotonin-2 (5-HT2) antagonists, ICI 169,369 and ICI 170,809, on 24 h EEG sleep-wake activity were studied in the rat. Both compounds caused a dose-related increase in the latency to rapid eye movement sleep (REMS) and significantly suppressed cumulative REMS time up to 12 h postinjection. In contrast, neither drug disrupted slow-wave sleep continuity in as much as the latency to non-REMS (NREMS) and cumulative NREMS time were unchanged. However, at the highest dose tested (20 mg/kg) ICI 170,809 did produce a significant increase in total NREMS time during the second half of the sleep-awake cycle. These results demonstrate effects of selective 5-HT2 antagonists on sleep in rats which appear to be specific for REMS behavior, suggesting that the priming influence of serotonin on REMS may involve 5-HT2 receptor subtypes. The relationship between the REMS suppressant actions of these compounds and their consideration as therapeutic agents in depression is discussed.
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PMID:Suppressant effects of selective 5-HT2 antagonists on rapid eye movement sleep in rats. 272 Apr 15

We investigated the mode of action of the potent antagonist ICI 170,809 in the 5-hydroxytryptamine (5-HT)2 receptor system of arterial smooth muscle. We used isolated preparations from rat tail artery and calf coronary artery with the endothelium rubbed off. In tail artery ICI 170,809 (0.3-30 nM) antagonized surmountably and nearly competitively the contractile effects of 5-HT (pKB = 10.0) and partially prevented the depression of 5-HT-induced contractions caused by methysergide. Increasing methysergide concentrations gradually prevented the protective effect of ICI 170,809. The combination of 30 nM ICI 170,809 with 300 nM of its demethylated analog ICI 169,369 (pKB = 8.8) caused surmountable blockade of the effects of 5-HT as expected from competition of the three drugs for the same receptor. In calf coronary artery ICI 170,809 (1-100 nM) reduced the maximum contractile response to 5-HT by 35% and caused competitive antagonism (pKB = 10.4) of the remaining 65% of the responses to 5-HT. ICI 169,369 (100 nM) completely prevented the depression of the maximum response to 5-HT caused by ICI 170,809. Methysergide (3 nM) depressed the maximum response to 5-HT by 65 and 30% in the absence and presence of ICI 170,809. The results are consistent with the existence of two interconvertible states R in equilibrium R' of the 5-HT2 receptor. The equilibrium of R in equilibrium R' is shifted toward R' by methysergide greater than ICI 170,809 much greater than ICI 169,369.
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PMID:Dimethylation of the activator ICI 169,369 results in a high-affinity partial deactivator, ICI 170,809, of the arterial 5-hydroxytryptamine2 receptor system. 276 Aug 51

3H-Lysergic acid diethylamide (3H-LSD) binding, a putative measure of 5-HT2 receptor binding, was studied in the blood platelets of 29 depressed patients and 24 normal controls. The Bmax (maximum number of 3H-LSD binding sites) in the blood platelets of depressed patients was significantly greater than that of normal volunteers. This increase in Bmax was due to an increase in female depressed patients only. Bmax was significantly lower in female compared to male normal controls but there was no difference between male and female depressed patients. There was also no difference in Kd (an inverse measure of affinity of 3H-LSD binding to its sites) between normal controls and depressed patients. The correlations between Bmax of 3H-LSD binding and the Bmax of the 3H-imipramine binding site or the Vmax of 5-HT uptake sites were not significant. The role of serotonergic processes in the psychobiology of depression is discussed.
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PMID:Increased serotonin2 (5-HT2) receptor binding as measured by 3H-lysergic acid diethylamide (3H-LSD) in the blood platelets of depressed patients. 292 43

5-HT2 receptor binding sites were measured (by saturation binding of [3H]ketanserin) in brain tissue obtained at postmortem from 19 suicide victims with definite evidence of depression and 19 sex and age-matched control subjects. Five of the suicide victims were receiving antidepressant drugs prior to death; 13 suicide victims had not been prescribed antidepressant or other psychoactive drugs recently and none were found in their blood at postmortem. The number of serotonin-2 (5-HT2) binding sites in frontal, temporal and occipital cortex and amygdala did not differ significantly between the depressed suicide victims and controls, either in the total suicide group or in the antidepressant drug-free suicides. The number of 5-HT2 binding sites in the hippocampus did not differ from controls in the total suicide group but was significantly lower (by 23%) in the antidepressant-free suicide group. The affinity of [3H]ketanserin binding did not differ from controls in the antidepressant-free suicides but was lower (increased Kd) in those subjects receiving antidepressant drugs. No correlation was found between the time of death and storage of tissue or the duration of tissue storage prior to assay and the number or affinity of 5-HT2 binding sites. A significant negative correlation was found between age of the subject and the number of 5-HT2 binding sites in the frontal and occipital cortex. The present study of suicide victims with definite evidence of depression do not confirm previous studies of increased numbers of 5-HT2 binding sites in suicide victims and suggest that these previous findings may be related to factors other than depression.
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PMID:Brain 5-HT2 receptor binding sites in depressed suicide victims. 335 70

The mode of action of ICI 169,369, a novel 5-hydroxytryptamine2 (5-HT2) receptor antagonist, was investigated in arterial muscle. Isolated preparations from calf coronary artery and from rat tail artery with the endothelium rubbed off were set up to contract isometrically with 5-HT. ICI 169,369 (1-3000 nM) antagonized surmountably and competitively the contractile effects of 5-HT in coronary artery (pKB, 9.1) and tail artery (pKB, 8.8). Methysergide antagonized unsurmountably 5-HT-induced contractions by reducing maximum effects to 25% (coronary artery: pIC50, 9.8) and 60% (tail artery: pIC80, 9.0). ICI 169,369 (100-300 nM) restored the maximum effects of 5-HT that had been depressed by methysergide (20 nM coronary artery, 100 nM tail artery). Preincubation with ICI 169,369 also prevented the methysergide-induced depression of the maximum effects of 5-HT. The protective effect of ICI 169,369 was overcome by high methysergide concentrations (up to 3 microM), suggesting competition between the two drugs for a common site. The data are consistent with an allosterically modulated interconversion of the 5-HT2 receptor between two states (R in equilibrium R'). ICI 169,369 competes with 5-HT for the 5-HT2 receptor. ICI 169,369 and methysergide also compete for an allosteric site of the 5-HT2 receptor system, thereby facilitating the highly active R-state and low active R'-state, respectively.
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PMID:ICI 169,369 is both a competitive antagonist and an allosteric activator of the arterial 5-hydroxytryptamine2 receptor system. 338 35

To test the hypothesis that a new potent and selective 5-HT2 receptor antagonist would be an excellent blocker of D,L-5-hydroxytryptophan (5-HTP)-induced response suppression in an animal model of depression, we administered LY53857 60 min prior to 5-HTP injections into rats working on an operant schedule for milk reinforcement. As predicted, LY53857 pretreatment significantly blocked 5-HTP depression (90%) in doses as low as 0.1 mg/kg ip. When the dose of LY58357 was further reduced to 0.025 mg/kg, blockade of 5-HTP-induced depression was still greater than 30%. In doses as high as 5.0 mg/kg, LY53857 alone had no effect on the baseline performance of rats working a VI 1 schedule. Pretreatment with desipramine (2.5 mg/kg), an antidepressant characterized as having major noradrenergic effects, did not significantly block the 5-HTP-induced depression. These data suggest that the 5-HTP-induced depression is mediated by serotonergic mechanisms involving 5-HT2 receptors, as LY53857 is a selective antagonist of these receptors. These data also support the suggestion, based on other published data from this laboratory, that some antidepressants are antagonizing 5-HT2 receptors in our animal model of depression and may also act in a similar manner in depressed patients. Thus, this new drug could be of interest as a possible antidepressant agent of the general type that was proposed earlier by Aprison and Hingtgen (1981).
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PMID:Blockade of a 5-hydroxytryptophan-induced animal model of depression with a potent and selective 5-HT2 receptor antagonist (LY53857). 387 59


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