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)

Lithium ion, which inhibits hydrolytic degradation of inositol monophosphates, is the most common therapeutic agent used in the control of bipolar disorder. There exists evidence that elevated elemental vanadium levels may play an etiological role in at least some forms of manic-depression. Here we demonstrate that vanadate treatment of intact cells from several different clonal lines synergistically induces substantial augmentation in neurotransmitter receptor-mediated or growth factor receptor-triggered inositol trisphosphate accumulation in situ. Furthermore, studies done using cellular extracts indicate that effects of vanadate treatment in situ may be due to its ability to inhibit hydrolysis of inositol 1,4,5-trisphosphate inositol 1,3,4-trisphosphate, and inositol 1,3,4,5-tetrakisphosphate in vitro. These results suggest that vanadate treatment may facilitate characterization of inositol phosphate metabolism and intracellular signaling.
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PMID:Vanadate amplifies receptor-mediated accumulation of inositol trisphosphates and inhibits inositol tris- and tetrakis-phosphatase activities. 131 22

Ondansetron (GR 38032) has potent and highly selective antagonist properties at the 5-hydroxytryptamine (5-HT, serotonin) 5-HT3 receptor. The selectivity ratio for ondansetron on 5-HT3 receptors compared with actions on other neurotransmitter receptor types is greater than 1,000. The antiemetic properties of ondansetron have been determined in ferrets against the nausea and vomiting induced by cisplatin, cyclophosphamide, and whole-body radiation. Ondansetron (intravenous 0.01 to 0.1 mg/kg or subcutaneous 0.1 to 0.5 mg/kg) or metoclopramide (1.0 to 4.0 mg/kg) cause dose-dependent inhibitions of the vomiting induced by each of these procedures. Unlike ondansetron, the effects of metoclopramide are accompanied by moderate to marked behavioral depression. Since metoclopramide is 50 times more potent on dopamine D2 receptors than on 5-HT3 receptors, the behavioral depression is likely due to profound blockade of dopamine receptors. The 5-HT3 receptors have been shown to be present peripherally on vagal afferent fibers and are densely located in the vomiting center of the hindbrain. The current hypothesis is that there may be both a peripheral and a central site of action for ondansetron and other 5-HT3 antagonists. The lack of antagonist activity on dopamine and other non-5-HT3 receptors indicates that, unlike metoclopramide, ondansetron will not cause extrapyramidal or other dose-limiting side effects.
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PMID:Pharmacology and preclinical antiemetic properties of ondansetron. 138 45

Abnormalities in several hypothalamic-pituitary-target organ axes in depression may reflect alterations in central neurotransmitter receptor function. As the alpha 2-adrenergic receptor has been implicated in a variety of neuroendocrine abnormalities in depression, we assessed the role of alpha 2-adrenoceptor dysfunction in mediating response abnormalities of growth hormone, cortisol, and prolactin after intravenous clonidine administration (an alpha 2-adrenergic receptor agonist) in 18 patients with major depression (12 with melancholic features, 6 without melancholic symptoms) and 9 healthy volunteers. In particular, we examined the hypothesis that these abnormalities might be more evident in patients with DSM-III melancholic depression. After clonidine, the mean growth hormone response was significantly lower in melancholic depressives compared to controls (p = 0.02), and the shape of the growth hormone response profile was also significantly different in melancholic patients (p = 0.04). There was an overall decrease in the mean cortisol concentration after clonidine in melancholic patients and control subjects (p = 0.02), as well as a larger cumulative prolactin response in melancholic patients compared to those without melancholic features (p = 0.02). The present results confirm prior observations of a blunted growth hormone response after clonidine and suggest that alterations in alpha 2-adrenergic receptor activity might also contribute to several neuroendocrine abnormalities in patients with melancholic depression.
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PMID:Multiple hormone responses to clonidine administration in depressed patients and healthy volunteers. 274 43

Fear is an adaptive response of the organism to external threat and the physiologic and behavioral responses to stimuli that induce fear involves activation of the sympathetic nervous system. Drugs that alter the function of two of the major brain monoamine neurotransmitter systems involved in sympathetic nervous system regulation (NE and 5-HT) have been shown to alter levels of "fear and anxiety" in laboratory animals, healthy humans, and patients. The relative clinical efficacy in the treatment of anxiety disorders with many of these drugs also emphasizes the importance of these two systems in anxiety. Recent advances in neuropharmacology have led to an improved understanding of how drugs that interact at specific NE and 5-HT receptors alter the function of these two neurotransmitter systems, and a few of the drugs that selectively interact at NE and 5-HT receptors have been used in studies of patients with anxiety disorders. Stimulation of the 5-HT system does not produce marked abnormalities in patients, but stimulation of the NE system does produce abnormal changes in measures of anxiety, somatic symptoms, blood pressure, and a plasma NE metabolite and cortisol levels in patients with panic disorder but not in patients with generalized anxiety disorder, obsessive-compulsive disorder, depression, or schizophrenia. This indicates that some patients with panic disorder have an abnormality in the regulation of the NE system that could explain many of the clinical features of this syndrome. Progress in assessing neurochemistry in the brains of living patients through brain imaging and new advances in the molecular biology of neurotransmitter receptor proteins will offer important new methods to be used in the study of these possible abnormalities.
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PMID:Monoamine receptor systems and anxiety disorders. 284 38

There is evidence that the abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function observed in patients with depression may be related to changes in central neurotransmitter receptor function. To evaluate this possibility further, the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride, which increases brain norepinephrine turnover, was administered to 40 patients with DSM-III major depression (18 melancholic, 22 nonmelancholic) and 16 healthy controls. Plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) level was measured as an index of noradrenergic function, and plasma cortisol level was used to assess the HPA response. Baseline cortisol levels were elevated in melancholic depressed patients, but not in nonmelancholic patients, when compared with healthy controls. The cortisol response to yohimbine was significantly greater in depressed patients than in controls, despite similar MHPG responses between groups. Since there is evidence that stimulation of postsynaptic alpha 2-adrenergic receptors inhibits HPA axis function, the abnormally increased cortisol response to the alpha 2-antagonist yohimbine suggests a relative subsensitivity of postsynaptic alpha 2-adrenergic receptors in depression.
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PMID:Alpha 2-adrenergic receptor function in depression. The cortisol response to yohimbine. 301 71

The effects of a series of tricyclic and non-tricyclic antidepressants on the transport of [3H]-serotonin into synaptosomal fractions from rat brain in vitro and in vivo are summarized. Differences in potency in vitro and in vivo would appear to be due partly to the presence of active metabolites, formed in vivo, that show different selectivities for the serotonin transport site. Evidence suggests that the initial reduction in serotonin turnover after acute administration of serotonin reuptake inhibitors is followed by a return to control values after the drug has been administered for at least 2 weeks. These changes in amine turnover are associated with normalization of both the serotonergic and beta-adrenergic receptor systems. Evidence suggests that changes in neurotransmitter receptor numbers and function of blood cells (platelets and lymphocytes) in depressed patients are possible state markers of the illness and that antidepressant efficacy may not be directly associated with specificity of amine reuptake inhibition. Studies also show that the bilaterally bulbectomized rat exhibits deficits in platelet and synaptosomal serotonin transport that resemble those shown in depressed patients. This animal model of depression may be useful not only for detecting putative antidepressants but also for studying the mode of action of such drugs during chronic administration.
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PMID:Pharmacological effects of serotonin reuptake inhibitors. 304 6

The large body of evidence presented indicates that in the brain the action of sex hormones cannot be thought as restricted to the regulation of endocrine functions and mating behavior. Estrogens and progesterone seem to act in numerous regions of the CNS to regulate motor as well as limbic functions. Furthermore, the data reviewed indicate that these hormones may modulate neuronal activity through a wide variety of mechanisms. More studies should focus on such mechanisms in order to better understand the role of sex hormones in the CNS and to devise ways of limiting their effects on depression, epilepsy etc. It is known that in peripheral target organs these hormones modulate cell activities by binding to specific receptors which can recognize the DNA sequence and activate the transcription of selected genes (135, 136). There is evidence supporting the hypothesis that this mechanism of action has been conserved also in the brain. First, the brain receptors for progesterone and estrogens are functionally and biochemically indistinguishable from those in the periphery (4, 5): they may be concentrated in neuronal nuclei and bind chromatin "in vitro" (7). Second, a temporal relationship has been observed between administration of steroids and the increase of polymerase II activity (137) and protein synthesis (4, 5). Third, various hormone-induced behaviors may be blocked by inhibitors of the protein synthesis (138, 139, 140, 141). However, sex hormones must be capable to regulate neuronal functions by mechanisms other then genomic. In fact, the topical application of estrogen or progesterone on nervous tissue results in a rapid change of membrane potential (60, 71). Such a rapid effect is not likely to be the consequence of nuclear action, but rather must be related to events occurring on the cell surface. It has been hypothesized that sex steroids affect the fluidity of the cell membrane, therefore modifying the ion transport or neurotransmitter receptor activity (142). If this were the case we would expect to observe a similar effect after application of any steroid. Experimental evidence demonstrates that not all the steroids affect the nervous membrane potential. Moreover, two steroids, estradiol and progesterone, have been described to modulate membrane potential in an opposite way (66, 67, 69, 75). At the moment, there is no evidence for the presence of steroid receptors on neuronal membranes which could mediate the described phenomena.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of female gonadal hormones in the CNS: clinical and experimental aspects. 389 52

Recent findings on neurotransmitter receptors are reviewed as they relate to current hypotheses of the etiology of depression and mechanism of action of antidepressant drugs. Two important research areas are 1) the finding that each synapse may have more than one neurotransmitter, and 2) data which link specific neurotransmitters and receptors to depressive illness and antidepressant drug response. A new hypothesis that has emerged from receptor studies is the neurotransmitter receptor hypothesis of antidepressant reaction, which states that antidepressants exert their effects by down-regulating neurotransmitter receptors. Research questions generated by these hypotheses are reviewed, and implications of findings in this area for the development of more effective, rapid-acting antidepressants are discussed.
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PMID:Regulation of neurotransmitter receptors by desipramine and other antidepressant drugs: the neurotransmitter receptor hypothesis of antidepressant action. 609 Apr 39

The principles and problems in neurotransmitter receptor radioligand binding studies are discussed. Various types of ligand-membrane interactions are described and criteria and ways for identification of specific receptor binding sites are evaluated. It is questioned whether the endogenous neurotransmitters must have binding affinities of nanomolar order for their receptor sites. The relationship between the numbers of receptor binding sites and functional activity of the receptors is investigated. Serotonin-S1 binding sites are sites labelled at nanomolar concentrations by [3H]serotonin. Various alleged roles for these sites are considered and found to be insufficiently substantiated. Therefore these sites should not yet be regarded as receptor sites. Serotonin-S2 binding sites are sites labelled by potent serotonin antagonists. The sites show a typical distribution in the mammalian brain and are present on blood platelets. The neuronal localization of the sites, investigated by lesion studies is discussed. Serotonin-S2 sites have a role in serotonin-induced behavioural excitation in laboratory animals. A presumed role for the sites in depression and anxiety is to be investigated. Serotonin-S2 sites were also shown to mediate serotonin-induced vasoconstriction and platelet aggregation. The sites were hypothesized from pharmacological and electrophysiological studies. Appropriate tools are lacking for a clear characterization of the multiple sites.
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PMID:Problems in in vitro receptor binding studies and identification and role of serotonin receptor sites. 614 78

The specific binding of 3H-imipramine to various brain regions of the rat is of high affinity (Kd = 4.0 nM), rapid and reversible. It was inhibited by tricyclic antidepressants at nanomolar concentrations and by atypical antidepressants at micromolar concentrations. The binding does not seem to be directly related to known neurotransmitter receptor systems. Specific 3H-imipramine binding sites were unequally distributed between the various brain regions and undetectable in the heart and vas deferens. Rats chronically treated with desipramine for three weeks had significantly less specific 3H-imipramine binding sites in the cortex than did control animals. It is concluded that these 3H-imipramine binding sites may be important in the study of depression and of the mechanism of action of antidepressant drugs.
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PMID:Specific tricyclic antidepressant binding sites in rat brain characterised by high-affinity 3H-imipramine binding. 737 14


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