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)

The development of direct serotonin agonists, selective inhibitors of serotonin uptake, serotonin receptor antagonists, and other drugs affecting serotonergic function has aided the study of physiologic functions of brain serotonin neurons in laboratory animals and the recognition and classification of serotonin receptor subtypes. Agents of these types are real or potential drugs for the treatment of psychiatric disorders (e.g., depression) and other disorders such as overeating, alcoholism, myoclonus, and chronic pain. In addition, the agents may permit assessment of the functional state of brain serotonin receptors in humans.
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PMID:Pharmacologic modification of serotonergic function: drugs for the study and treatment of psychiatric and other disorders. 351 85

The role of antidepressants in bringing about adaptive changes in peripheral and central neurotransmitter receptors is briefly reviewed and extended to show how changes in platelet and lymphocyte adrenoceptor and serotonin receptor activity may correlate with the depressed state and normalise following effective treatment. By contrast, the 3H-imipramine binding sites on the platelet membrane do not change following successful treatment and may therefore reflect a trait-dependent (genetic) change. The neuroendocrine markers, such as the dexamethasone suppression test (DST), have the advantage over the receptor markers in that they require less sophisticated laboratory facilities. It is concluded that a better insight into the aetiology and progress of depression may be gained by combining receptor markers with such neuroendocrine markers as the DST.
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PMID:Neurotransmitter markers of depression. 615 35

The ability of an intensive glucocorticoid regimen (i.e., triamcinolone diacetate, 8 mg/kg i.m./7 days) to modify the lumbar spinal monosynaptic reflex response to serotonergic and noradrenergic agents has been examined in unanesthetized acute spinal (C-1 sectioned) cats. Triamcinolone pretreatment enhances the 2N facilitatory actions of amitriptyline (AMIT), 5 mg/kg i.v., when given after D,L-5-hydroxytryptophan (5--HTP), 50 mg/kg i.v., as compared to untreated control preparations. Subsequent administration of methysergide, a serotonin receptor blocking drug, in a dose of 1 mg/kgh i.v. promptly and completely reverses the monosynaptic response increase by AMIT in untreated animals, but not in the glucocorticoid treated ones. In contrast, the monosynaptic facilitation normally produced in untreated preparations by methoxmine (MX), 1 mg/kg i.v., a centrally active noradrenergic agonist, is prevented as a result of triamcinolone dosing. These results demonstrate a glucocorticoid effect on spinal biogenic amine function such that serotonergic monosynaptic reflex activation is enhanced while noradrenergic reflex stimulation is depressed. Furthermore, they suggest that the elevations in plasma cortisol in certain cases of psychiatraic depression may; contribute to alterations in central biogenic amine synaptic activity.
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PMID:Glucocorticoid effects on serotonergic and noradrenergic facilitation of spinal monosynaptic transmission. 625 3

Acute pretreatment with clinically equivalent doses of antidepressive drugs has been observed to block D,L-5-hydroxytryptophan (5-HTP) induced behavioral depression in rats working on a food-reinforced operant schedule. Data from studies designed to distinguish presynaptic from postsynaptic events, indicated that the antidepressants were acting in part as blockers of postsynaptic serotonergic receptors. Using the same 5-HTP model of depression, we studied both the chronic and acute effects of a recently introduced antidepressant, triazolopyridine compound. Rats working for milk reinforcement and exhibiting behavioral depression following administration of 50 mg/kg 5-HTP were pretreated (one hr before 5-HTP) with 1, 2, or 4 mg/kg trazodone with resulting blockade of 5-HTP induced depression of 35, 62 and 70% respectively. Chronic administration of trazodone (2 mg/kg trazodone/day) also resulted in a significant blockade of the 5-HTP effect (75%). Neither 2 mg/kg or 4 mg/kg trazodone was found to potentiate the shorter period of depression following 25 mg/kg 5-HTP. Chronic treatment with the antidepressant drugs, amitriptyline or mianserin also blocked 5-HTP depression. Thus, as in our earlier studies, these data suggest an important postsynaptic mechanism associated with chronic administration of trazodone, amitriptyline and mianserin which could be implicated in the therapeutic effectiveness of these drugs. The potency of trazodone in relation to other antidepressant drugs in our behavioral model of depression paralleled their potency in displacing radioligand binding to 5-HT receptors, and gives additional support for the new hypersensitive postsynaptic serotonin receptor theory of depression.
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PMID:Postsynaptic serotonergic blockade following chronic antidepressive treatment with trazodone in an animal model of depression. 660 37

Although central serotonergic systems appear to be linked importantly to the mechanism of action of a variety of hallucinogenic drugs, the nature of this interaction has remained unclear. In the present study, the question of whether the critical link is presynaptic or postsynaptic was examined in cats. Behaviorally inactive doses (1.0 mg/kg) of the serotonin receptor antagonists mianserin, ketanserin or metergoline effectively blocked behavior, as measured by the cat limb flick response, elicited by either LSD (50 micrograms/kg) or DOM (250 micrograms/kg) but not that resulting either from lisuride (50 micrograms/kg) or a high dose of apomorphine (4 mg/kg). Pretreatment with 1.0 mg/kg of mianserin, which completely attenuated LSD's behavioral effect, failed to alter LSD-induced depression of mesencephalic serotonergic neuron discharge. These results demonstrate that at least some of the behavioral effects of LSD can be blocked by pharmacological antagonism of postsynaptic serotonin receptors which leaves LSD's presynaptic effect unaffected. Thus, the behavioral, and possibly psychoactive, effects of hallucinogens appear to be attributable to an action at 5HT2 receptors, presumably located postsynaptically.
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PMID:Some behavioral effects of hallucinogens are mediated by a postsynaptic serotonergic action: evidence from single unit studies in freely moving cats. 674 19

To further test the new hypersensitive postsynaptic serotonin (5-HT) receptor theory of depression bases on or animal model, it was necessary to demonstrate that some of the currently used antidepressive drugs can block D,L-5-hydroxytryptophan (5-HTP) induced depression acting through postsynaptic rather than presynaptic mechanisms. Rats working for milk reinforcement and exhibiting behavioral depression following administration of 5-HTP (IP) were pretreated (1 hour before the 5-HTP injection) with fluoxetine (5 mg/kg IP) or methysergide (5 mg/kg IP) to establish a behavioral basis for distinguishing between pre- and postsynaptic events, respectively. Fluoxetine, a known specific uptake blocker of 5-HT, potentiated the depressive effect of 12.5 mg/kg 5-HTP by 200%. Methysergide, a postsynaptic blocker of 5-HT, almost completely (93%) abolished the depressive effect of 50 mg/kg 5-HTP. Since acute pretreatment with comparable clinical doses of the antidepressive drugs, mianserin, amitriptyline, imipramine, or iprindole, resulted in blockade of the 5-HTP induced depression by 70, 50, 40, and 20% respectively, these drugs can act as antagonists of 5-HT at the postsynaptic serotonin receptor. When these results are viewed in terms of recent data reported from CNS binding studies, the therapeutic effects of some antidepressants may be explained by their postsynaptic rather than presynaptic effects at central serotonergic receptors.
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PMID:Postsynaptic action by four antidepressive drugs in an animal model of depression. 697 69

Antidepressant drugs are effective for about three in four people with depression. For reasons that are not understood, individual patients who do not respond to one drug often respond to another. Differences in mechanisms of action may thus be important in determining treatment success or failure. In addition to efficacy, drug side effect profile also determines treatment outcome. In general, the fewer or less severe the side effects of a drug, the greater the degree of compliance with treatment. A major consequence of the introduction of selective serotonin-specific antidepressants is greater patient acceptance due to fewer side effects. Still, some patients are unable to tolerate the nervousness, insomnia, or sexual dysfunction associated with these drugs. Drugs that are even more specific in that they act on specific serotonin receptor subtypes, rather than only by blocking serotonin uptake, may provide efficacy and fewer side effects for patients who do not respond to or tolerate less specific agents.
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PMID:The potential benefits of serotonin receptor-specific agents. 752 27

A patient with post-stroke depression following infarction of the left basal ganglia is described. The patient's depression remitted during a 6-week double-blind treatment trial while receiving placebo medication. Cortical S2-receptor binding that was measured using 11C-N methyl spiperone and positron emission tomography (PET), increased in the left temporal cortex by more than 25% during the treatment trial. The change in serotonin receptor binding and its relationship to the improvement in mood observed in this patient are consistent with previously published data demonstrating a correlation between serotonin receptor binding in the left temporal cortex and severity of symptoms of depression.
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PMID:Spontaneous remission of post-stroke depression and temporal changes in cortical S2-serotonin receptors. 758 Jan 80

Disturbances of serotonergic pathways have been implicated in a wide variety of neuropsychiatric disorders such as depression, anxiety, migraine, and substance abuse. Genetic variation in genes coding for serotonin receptor proteins might well be involved in the genetic predisposition to these diseases and/or of pharmacogenetic relevance. Genomic samples from 46 unrelated healthy subjects were investigated by single-strand conformation analysis (SSCA) to screen for genetic variation in the human serotonin 1D beta (5-HT1D beta) receptor gene. Overlapping PCR (polymerase chain reaction) fragments covered the whole coding sequence as well as 5' untranslated regions of the 5-HT1D beta gene. Four nucleotide sequence variants were found: a coding mutation in nucleotide position 371 which leads to an amino acid exchange (Phe-->Cys) in position 124 of the receptor protein and three mutations in the 5' flanking region. For all mutations specific PCR-based assays were developed which allow rapid genotyping in populations and families. To our knowledge, the Phe-124-Cys substitution is the first natural occurring molecular variant which has been identified for the 5-HT1D beta receptor so far.
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PMID:Identification of genetic variation in the human serotonin 1D beta receptor gene. 780 50

Serotonin (5-hydroxytryptamine; 5-HT) has been implicated in a large number of psychophysiologic processes including the regulation of sleep, appetite, mood, aggression, perception, memory, and anxiety. To mediate this large array of physiologic processes, at least 14 separate 5-HT receptors have evolved, which are divided into seven main families. Not surprisingly, alterations of 5-HT receptor activity have been shown to occur in many psychiatric diseases including anxiety, depression, eating disorders, schizophrenia, personality disorders, and many drug-induced psychotic states. Additionally, a number of effective psychopharmacologic agents for diseases as diverse as schizophrenia and anxiety have been developed which either specifically alter brain levels of serotonin or bind to 5-HT receptor subtypes. This review article summarizes recent advances in the burgeoning field of serotonin receptor pharmacology and integrates this information into a coherent perspective on the importance of serotonergic agents for clinical psychiatry.
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PMID:Multiple serotonin receptors: clinical and experimental aspects. 780 91


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