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)

In Japan, fifteen drugs, including tricyclic and non-tricyclic antidepressants or an MAO inhibitor, are clinically available for treatment of depression. However, the pharmacological mechanism(s) of their antidepressive effect remain uncertain. "Receptor hypothesis" that functional changes of monoamine receptors after chronic treatment, such as down-regulation of beta-adrenoceptor or 5-HT2 receptor, bring about a therapeutic effect, seems to be unsatisfactory. Recent studies focus on interaction between antidepressants and intracellular signal transduction pathways. For effective and safe uses of antidepressants, especially in aged patients or those with hepatic and renal diseases, pharmacokinetics such as distribution, protein binding and metabolism must be well understood. In this paper, pharmacokinetic characteristics of antidepressants are also reviewed.
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PMID:[Antidepressant and antimanic drugs--pharmacological mechanisms and pharmacokinetics]. 800 87

d-Amphetamine (DEX) and phencyclidine (PCP) increased motor activity in rats as measured in automated activity cages. Analysis of the stimulation indicated that both drugs increased horizontal activity (total activity), locomotion, and peripheral activity. However, DEX increased while PCP decreased the incidence of rearing. The ability of different drugs to antagonise DEX- and PCP-induced increases in total activity (called stimulation) was measured. Dopamine (DA) D1 receptor antagonists (SCH23390, NNC-01-0112) were 7-8 times more potent in blocking DEX than PCP. DA D2 receptor antagonists (raclopride, remoxipride, haloperidol) were only 1-2 times more potent against DEX-induced stimulation. Nonselective DA receptor antagonists were also tested. Chlorpromazine was more potent against DEX than against PCP. Buspirone and sertindole were slightly more potent in blocking PCP than DEX. Ritanserin (5-HT2 receptor antagonist) was inactive against both stimulants. 8-OH-DPAT (5-HT1A receptor agonist) potentiated the stimulant effects of DEX and PCP. Prazosin (alpha 1-adrenergic receptor antagonist) partially blocked both DEX and PCP. Most drugs tested depressed spontaneous motor activity. Remoxipride and sertindole, however, caused very little depression even at doses several times higher than those needed to block DEX or PCP. The data show clear pharmacological differences between DEX- and PCP-induced stimulation.
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PMID:Dopamine receptor antagonists block amphetamine and phencyclidine-induced motor stimulation in rats. 809 Aug 16

Long-term exercise is associated with an antidepressant effect in patients with mild to moderate forms of nonbipolar depression and appears to be a promising new approach to its treatment. Adaptive changes in serotonin (5-HT) receptor functioning appears to play an important role in mediating the action of various antidepressant treatments. We investigated the adaptive changes in behavioral sensitivity of the 5-HT receptor subtype following 4 weeks of swimming exercise in normal rats, as well as in an animal model of depression (3 week, variety of chronic stressors). 5-HT1A autoreceptor sensitivity was assessed by hyperphagic response induced by 8-OH-DPAT (0.25 mg/kg, IP); 5-HT1A postsynaptic receptor by 5-HT syndrome induced by 8-OH-DPAT (0.75 mg/kg, IP), and 5 Me-ODMT (5 mg/kg, IP); and 5-HT2 receptor by wet dog shakes response induced by quipazine (1 mg/kg, IP) and 5MeODMT (5 mg/kg, IP). It was observed that exercise training in normal rats resulted in enhanced sensitivity of the 5-HT2 receptors along with subsensitivity of 5-HT1A autoreceptors. Exercise, given prophylactically along with chronic stressors, was able to prevent the development of behavioral deficit in the open-field test, and the animals developed remarkably enhanced sensitivity of 5-HT2 receptors. This adaptive supersensitivity of 5-HT2 receptor is also seen after various antidepressant treatments and may play an important role in mediating the antidepressant action of exercise.
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PMID:Physical exercise as a novel antidepressant agent: possible role of serotonin receptor subtypes. 815 73

Many studies have demonstrated pharmacologic similarities between platelet and brain 5-HT2 binding sites. Therefore it may be possible to use platelets as a model for the central serotonergic neuron. Accordingly, a previous report (Kusumi et al. 1991b) about elevated [Ca2+]i after serotonin stimulation in platelets of depressed patients was interpreted as further evidence for enhanced serotonergic sensitivity in depression. However, a very recent study showed an enhanced thrombin-induced platelet Ca2+ response, rather suggesting abnormalities of intracellular Ca2+ regulation in affective disorders. In the present study we have determined 5-HT2- and thrombin-induced Ca2+ responses in platelets and additionally phytohemagglutin (PHA)-induced Ca2+ increase in lymphocytes of medicated depressed patients (8 mono- and 2 bipolar, HRSD > 17) and of ten sex- and age-matched controls. The results showed no significant difference in basal calcium levels between the two groups and no significant difference in the Ca2+ response to thrombin although the response was higher in the patients. The Ca2+ increase after serotonin stimulation in depressed patients was significantly (P < 0.05) higher than in healthy controls. By contrast, the Ca2+ response to PHA in lymphocytes was significantly decreased in the patients. Our data confirm elevated Ca2+ responses after 5-HT2 receptor activation even in mediated depressed patients. However, Ca2+ responses in lymphocytes were decreased. Together with the observations of an enhanced Ca2+ response in platelets after thrombin stimulation, we speculate that the findings rather suggest alterations of [Ca2+]i regulation in depression than specific changes of serotonergic sensitivity.
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PMID:Platelet and lymphocyte free intracellular calcium in affective disorders. 817 37

While headache is a documented side effect of electroconvulsive therapy (ECT), there is little information on this phenomenon. Studies of the mechanisms of ECT as a treatment for depression indicate that alterations in serotonergic neurotransmission appear to be related to its efficacy. While ECT and many of the antidepressant drugs have similar effects on serotonergic transmission, they are notably different in the changes they induce in type 2 receptors for 5-hydroxytryptamine (5-HT). ECT upregulates 5-HT2, and antidepressants down regulate the receptor's expression. 5-HT2 receptor sensitization has been associated previously with headache genesis, which may explain why ECT induces headache, and amitriptyline relieves headache. In our study we surveyed 98 patients retrospectively about their experiences with headache prior to and following ECT. Of the 54 patients who submitted properly completed questionnaires, five reported new onset of headaches following ECT, four reported exacerbation of a previous headache problem, and two reported their headaches improved. The patients experienced changes in the character or location of pain, with a tendency to progress from tension-type to migrainous headache. In all but two cases these developments persisted at least eight months after ECT. We discuss the possible reasons and significance of our findings.
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PMID:Headache and electroconvulsive therapy. 820 Jul 90

This study was undertaken to investigate the effect of chronic treatment with fluoxetine, a selective serotonin uptake inhibitor used widely in the treatment of depression, on the distribution and density of 5-HT uptake sites, 5-HT2 receptors, and vesicular amine uptake sites in rat brain. Fluoxetine (10 mg/kg i.p.) was administered daily for 21 days. The density of 5-HT uptake sites labelled by [3H]paroxetine, 5-HT2 receptors labelled by [3H]ketanserin in presence of tetrabenazine and vesicular amine uptake sites labelled by [3H]ketanserin in the presence of mianserin were measured by quantitative autoradiography in 22 areas of rat brain, using coronal tissue sections. Chronic administration of fluoxetine produced significant increases in the density of 5-HT uptake sites in layers of frontoparietal cortex (by 32-43%), of striate cortex (by 55%), in CA1 field of hippocampus (by 111%) and in superior colliculus (by 20%). Fluoxetine treatment also resulted in upregulation of 5-HT2 receptors in layers of frontoparietal cortex (31-38%) and in CA2-3 fields of hippocampus (by 39%). The density of tetrabenazine-sensitive vesicular amine uptake sites in the caudate-putamen was also significantly increased (by 66%). The observed alterations in 5-HT uptake site and 5-HT2 receptor densities are likely a part of adaptive neuronal changes that occur after chronic administration of fluoxetine and may be related to the antidepressant effect of the drug.
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PMID:Chronic fluoxetine treatment upregulates 5-HT uptake sites and 5-HT2 receptors in rat brain: an autoradiographic study. 824 54

Twenty-four norbornane analogues of tryptamine and 5-methoxytryptamine were investigated for affinity at 5-HT2 receptors of the rat tail artery and proved to be weak non-competitive antagonists of 5-HT. Compound 12 which displayed a marked depression of the concentration-effect curves, was examined for potential interaction with the allosteric binding site of the 5-HT2 receptor. The effects elicited by 12, in the presence and absence of the allosteric activator ketanserin, were atypical and must be attributed to a mechanism, unknown up to now. In radioligand displacement experiments binding data for a set of nine compounds were determined at 5-HT1-like, 5-HT2 and 5-HT3 receptors, indicating subtype selectivity for some analogues. The binding affinity of 8 at 5-HT3 receptors which was comparable with the affinity of the selective 5-HT3 agonist 2-methyl-5-HT, could not be demonstrated on the longitudinal muscle strip of the guinea-pig ileum, partially due to the M3 antimuscarinic activity of 8. Functional studies on the rat oesophageal tunica muscularis mucosae did not reveal 5-HT4 agonist properties for two analogues of 5-methoxytryptamine (8, 16).
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PMID:Selectivity of sterically fixed tryptamine and 5-methoxytryptamine derivatives for serotonin receptor subtypes, II: Structure-activity relationships and in vitro pharmacology of N-alkyl- and N,N-dialkyl-3- indolylbicyclo-[2.2.1]-heptane-2-amines. 827 71

Abnormalities of brain serotonin (5-hydroxytryptamine; 5-HT) metabolism have been proposed as the neurobiological basis of a vulnerability to depression and of a long-standing tendency toward impulsivity and aggression. Results from studies that have employed a variety of 5-HT measures, including the assessment of cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations, 5-HT uptake site densities, and 5-HT2 receptor densities in brain tissue and on platelets, and prolactin increases following fenfluramine administration, provide support for these two hypotheses. The goal of future research should be to better define the pathophysiological role of 5-HT dysfunction for both mood instability and impulsivity, in the service of developing improved treatments for these psychopathological conditions.
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PMID:Abnormalities of serotonin metabolism and nonpsychotic psychiatric disorders. 831 85

Serotonin 5-hydroxytryptamine (5-HT)2 receptors are implicated in the etiology of mental disease and depression. Drugs that interact with the 5-HT2 receptor are used therapeutically to treat such illnesses, and their mechanisms of action are of great interest. In this study 5-HT2 receptor-ligand interactions were examined by site-directed mutagenesis in which three aspartic acid to asparagine mutants (Asn-120, Asn-155, and Asn-172) were created and expressed in NIH3T3 cells. The Asp-120 to asparagine mutant exhibited the same affinity for 125I-lysergic acid diethylamide (125I-LSD) as did the wild-type receptor and showed a decreased and GTP-insensitive binding affinity for the agonists 5-HT and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (approximately 10-fold) and the antagonists ketanserin and mianserin (approximately 10-fold) but not spiperone. The mutation also abolished agonist-stimulated formation of [3H]polyphosphoinositides (PI). The Asn-155 mutant showed reduced binding affinity for 125I-LSD (Kd, 2.8 nM versus 0.6 nM for the wild-type receptor) and had reduced affinity for agonists (approximately 30-fold) and for antagonists (14-75-fold). However, the Asn-155 receptor retained GTP sensitivity and the ability to stimulate PI formation. The Asn-172 mutant retained the wild-type Kd value for 125I-LSD, exhibited only approximately 5-fold reduced affinity for 5-HT and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane while retaining GTP-sensitive agonist binding showed no change in affinity for ketanserin, and had a small decrease in mianserin and spiperone binding (approximately 6-fold). The Asn-172 receptor also retained the ability to form PI. These results indicate that Asp-120 is necessary for allosteric activation of the guanine nucleotide-binding protein. Asp-155 is necessary for high affinity binding, probably by acting as a counterion for the amine group of the ligand. The different effects of the three mutations on ketanserin, mianserin, and spiperone binding affinity suggest that these antagonists may share overlapping but different binding domains. The information provided by this study may facilitate the design of therapeutic site-selective compound based on the structure of the 5-HT2 receptor.
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PMID:Site-directed mutagenesis of the serotonin 5-hydroxytrypamine2 receptor: identification of amino acids necessary for ligand binding and receptor activation. 831 24

The human platelet 5-HT2 receptor may resemble a peripheral model of central 5-HT2 binding sites and has been linked to changes in 5-HT2 receptor function in depression. Therefore, evaluation of the human platelet 5-HT2 binding characteristics is important. Comparing [3H]ketanserin and [3H]LSD as ligands clearly indicated [3H]LSD as ligand of choice for binding studies dealing with the human platelet 5-HT2 receptor. [3H]LSD binding was specific, saturable, and depended upon incubation time, protein concentration and previous handling of tissue, i.e., use of fresh or frozen tissue. In contrast, studies with [3H]ketanserin were unsatisfactory. Although mean receptor densities and affinities have been relatively constant between individuals and over time in healthy subjects with [3H]LSD, examination of the individual data showed considerable variations within single subjects. Thus, KD ranged between 0.50 and 0.68 nM, and Bmax was in the range of 64.9 to 97.1 fmol/mg protein in healthy individual subjects. Therefore, we recommend [3H]LSD as ligand of choice to study platelet 5-HT2 receptor binding in humans. Furthermore, repeated measurement of individual data over time should be interpreted cautiously, especially when data from depressed patients are under examination.
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PMID:Human platelet 5-HT2 receptor binding sites re-evaluated: a criticism of current techniques [corrected]. 832 69


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