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 potential role of autoreceptors in regulating the activity of serotonin-containing nucleus raphe dorsalis (RD), raphe medianus (RM) and raphe pallidus (RPA) neurons was examined by recording the activity of these neurons under a variety of conditions both in vivo and in vitro. Raphe neurons recorded in vivo displayed the characteristic slow, rhythmic discharge pattern previously described for rat and cat raphe cells. The activity of these neurons was suppressed in a dose-dependent manner by tryptophan, LSD and chlorimipramine administered intravenously. There were no significant changes in the spontaneous discharge rate of raphe neurons over time when recorded in vitro, even though tissue serotonin and its metabolite, 5-hydroxyindoleacetic acid, decreased dramatically. RPA neurons fired significantly faster than either RD or RM neurons both in vivo and in vitro. Prior depletion of brain serotonin by p-chlorophenylalanine administration resulted in no significant change in raphe unit activity recorded in vitro. Elevation of brain serotonin by monoamine oxidase inhibition produced a total inhibition of raphe unit activity in vitro. Similarly, increasing the concentration of serotonin in the tissue slice by adding serotonin directly to the incubation medium resulted in a profound, though transitory, depression of unit activity. This depressant effect of serotonin was rapidly reversible upon drug wash-out. Serotonin receptor blockers, methiothepin, cypoheptadine, and methysergide, produced no significant change in unit activity. The serotonin reuptake blocker, fluoxetine, produced a total inhibition of raphe unit activity in all three nuclei in vitro. These data suggest that excess serotonin suppresses the activity of raphe neurons, apparently by an action on autoreceptors, but that a deficiency, or normal concentration, of serotonin does not influence the spontaneous activity of these cells. The data also show that RD and RM are much more sensitive to the depressant effects of serotonin than the caudal RPA neurons. More generally, these studies provide a data base for examining the electrophysiological and pharmacological characteristics of serotonergic neurons in the three major serotonin-containing nuclei in mouse brain. The mouse has proven to be a much easier species than the rat to use in these types of studies, based on the finding that mouse brain slices are more viable in vitro than are rat brain slices.
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PMID:A comparison of the electrophysiological and pharmacological properties of serotonin-containing neurons in the nucleus raphe dorsalis, raphe medianus and raphe pallidus recorded from mouse brain slices in vitro: role of autoreceptors. 243 25

It was shown previously that focal cortical freezing lesions in rats cause widespread depression of local cerebral glucose utilization (LCGU) in cortical areas of the lesioned hemisphere. This was interpreted as reflecting functional depression. The underlying mechanisms were postulated to involve alterations of biogenic amine systems. Accordingly, levels of serotonin (5-HT), its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and its precursor tryptophan were determined by an HPLC method with electrochemical detection in frontoparietal cortical areas of both hemispheres at 4 h and 1, 3, 6, 8, and 10 days after a unilateral cortical freezing lesion. The 5-HT content was significantly lower than normal in the lesioned hemisphere only at 24 h, whereas the 5-HIAA level peaked at 24 h but was significantly elevated above normal values between 4 h and 6 days after lesioning. No changes were noted in 5-HT and 5-HIAA contents in the hemisphere contralateral to the lesion. These results indicate that cortical 5-HT metabolism is increased throughout the lesioned hemisphere of a focally injured brain. The increase in tryptophan content of the lesioned brain appeared to have a time course more closely related to previously demonstrated changes in cortical LCGU than to the increase in 5-HIAA content.
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PMID:Effects of injury on the indoleamines in cerebral cortex. 243 85

Plasma concentrations of nortriptyline (NT) and its major metabolite 10-hydroxy-NT (10-OH-NT) were measured in 30 patients with depression, treated with NT for 3 weeks. Nine patients who recovered completely had plasma concentrations of NT and 10-OH-NT ranging from 358 to 728 nmol/L and from 428 to 688 nmol/L, respectively. Of the 21 patients who did not recover completely, only four had plasma concentrations within the window limited by these two plasma concentration ranges. A correlation was found between the degree of amelioration and the plasma concentration of NT (rs = 0.469; P less than 0.01). Lumbar punctures were performed in 26 patients before and after 3 weeks of NT treatment. During treatment there was a 30.9% mean decrease in the noradrenaline metabolite 4-hydroxy-3-methoxyphenylglycol (HMPG) in cerebrospinal fluid (CSF). We could not evaluate the extent to which this decrease was caused by NT or 10-OH-NT, respectively, because both are strong inhibitors of noradrenaline uptake. The ratio between the concentration of NT and 10-OH-NT in CSF correlated to the reduction of HMPG in CSF (r = 0.397; P less than 0.05) and to the amelioration of depression (rs = 0.623; P less than 0.001). This might indicate that NT and 10-OH-NT interact on the noradrenaline system in a nonadditive way. During treatment there was a 15.2% decrease in CSF concentration of the serotonin metabolite 5-hydroxyindoleacetic acid. The reduction was significantly correlated to the CSF concentration of NT but not to that of 10-OH-NT. This is in accordance with the fact that NT is a more potent inhibitor of serotonin uptake than is 10-OH-NT. The dopamine metabolite homovanillic acid in CSF decreased significantly by 10.0%. The biochemical data indicate that noradrenergic, serotoninergic, and dopaminergic systems are affected by NT treatment and that 10-OH-NT might be more selective on noradrenergic neurons than the parent drug.
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PMID:Clinical and biochemical effects during treatment of depression with nortriptyline: the role of 10-hydroxynortriptyline. 243 50

Cerebrospinal fluid (CSF) amine metabolites were measured in 37 male subjects with major depressive disorder. Scores on the Hamilton Rating Scale for Depression (HRSD) correlated significantly with 5-hydroxyindoleacetic acid (5HIAA) and with homovanillic acid (HVA). In addition, the single suicide item of the HRSD correlated significantly with 5HIAA. Further, 5HIAA and HVA correlated significantly with each other. There was a significant positive correlation between HVA and two HRSD items, the depersonalization/derealization item and the paranoid item. Since lumbar CSF metabolite concentrations may reflect central nervous system activity of parent amines, these data suggest a relationship between depression and decreased dopaminergic and serotonergic activity.
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PMID:CSF amine metabolites and depression. 244 71

Following a finding that single doses (approximating to average intakes and to potential 'over-use') of aspartame administered orally to mice caused significant increases in norepinephrine and dopamine concentrations in various brain regions, the effect of repeated exposure to aspartame was studied. Male CD-1 mice were given a daily oral dose of 0, 13, 133 or 650 mg/kg for 30 days and 1 day after the last dose the animals were decapitated and their brain regions were quickly isolated. Analyses of the different regions for catecholamine and indoleamine neurotransmitters and their major metabolites indicated that the increases in adrenergic chemicals observed shortly after a single exposure were not apparent after repeated dosing. In contrast, concentrations of serotonin and its metabolite, 5-hydroxyindoleacetic acid, were decreased in several regions. An increased supply of phenylalanine may be responsible for a decrease in tryptophan uptake by the brain tissue or for a depression in tryptophan conversion to serotonin.
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PMID:Effects of repeated doses of aspartame on serotonin and its metabolite in various regions of the mouse brain. 244 82

Dopamine and serotonin systems are morphologically interconnected in the midbrain. Several studies have also demonstrated a functional relationship between these two monoamine systems. Concentrations of their metabolites, 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA), consistently correlate with one another in human cerebrospinal fluid. Previous studies of the effects of antidepressants on the dopamine and serotonin systems have focused on the two systems in isolation without considering the interactions between the two. One way of taking this interaction into account may be to form a ratio of dopamine and serotonin measures. The present study measured HVA and 5HIAA in cerebrospinal fluid of 31 patients with depression and 12 patients with Alzheimer's disease before and after treatment with a variety of antidepressant drugs. The ratio of HVA/5HIAA was able to discriminate much more powerfully between effects of different drugs than HVA or 5HIAA examined separately.
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PMID:The effects of antidepressants on the cerebrospinal fluid homovanillic acid/5-hydroxyindoleacetic acid ratio. 244 15

Clinical studies of monoamine neurotransmitter function in depression have concentrated on individual monoamines without focusing on interactions between monoamine systems. Virtually all modern studies have found significant correlations between monoamine metabolite concentrations in cerebrospinal fluid (CSF). These correlations should in part reflect interactions between central monoamine systems. In the present analysis, CSF had been obtained from depressed patients before (n = 40) and after (n = 36) antidepressant treatment. The patients were grouped based on their response to treatment. Absolute concentrations of CSF monoamine metabolites (homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethyleneglycol) did not differ between the two groups before or after treatment. However, when correlations between metabolites were compared, nonresponders to treatment differed considerably from responders. In responders, as in previously described normal populations, all three metabolites correlated with one another before and after treatment, and treatment-induced changes in metabolite concentrations also correlated with one another. In contrast, metabolites in nonresponders did not correlate with one another before treatment, nor did treatment-induced changes correlate with one another in this group. Furthermore, correlations between treatment-induced changes in metabolites differed significantly between responders and nonresponders, and there was a trend for pretreatment correlations to differ as well. The lack of correlation between monoamine metabolites in nonresponders suggests that interactions between monoamine systems may be disrupted in these individuals. Using CSF metabolite correlations to study neurotransmitter interactions may have clinical relevance and yields information not available from examining neurotransmitters in isolation.
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PMID:Monoamine neurotransmitter interactions and the prediction of antidepressant response. 244 88

The response of brain dopaminergic and serotonergic systems to the amphetamine-like designer drugs, 3,4-methylenedioxyamp amphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA), was investigated and compared to methamphetamine (METH). Like METH, single or multiple doses of either drug caused marked reductions in both tryptophan hydroxylase (TPH) activity and concentrations of 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA) in several brain regions. The reduction in 5HT content corresponded to the depression of TPH activity in all regions examined. In contrast to METH, which induced pronounced deficits in dopaminergic neuronal markers, repeated doses of MDA or MDMA did not alter striatal tyrosine hydroxylase (TH) activities or reduce striatal dopamine concentrations. A single dose of MDA or MDMA significantly elevated striatal dopamine content; however, after repeated drug administrations dopamine concentrations were comparable to control values. The effects of MDA or MDMA administration in the rat brain are reminiscent of those elicited by p-chloroamphetamine, a presumed serotonergic neurotoxin.
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PMID:The effects of amphetamine-like designer drugs on monoaminergic systems in rat brain. 244 19

It was shown previously that focal cortical freezing lesions in rats cause widespread decrease in local cerebral glucose utilization (LCGU) in cortical areas of the lesioned hemisphere. This was interpreted as reflecting a depression of cortical activity. It was then demonstrated that cortical serotonin (5-HT) metabolism was increased throughout the lesioned hemisphere of a focally injured brain. To find out if the changes in the serotonergic system are of functional importance and mediate the observed changes in LCGU, the effects of the inhibition of 5-HT synthesis with p-chlorophenylalanine (PCPA) on cerebral metabolism and biogenic amine content in injured brain were studied. PCPA in doses up to 300 mg/kg had little, if any, effect on LCGU in intact brain and in doses up to 100 mg/kg did not modify the depressed LCGU in injured brain. In doses of 200 and 300 mg/kg, PCPA selectively increased cortical glucose utilization in the lesioned hemisphere where it was depressed following injury. PCPA decreased 5-HT levels in the cortical and raphe areas of both intact and injured brain in a dose-dependent manner. However, at doses of PCPA ineffective on LCGU (50 and 100 mg/kg), traumatization still resulted in increased 5-HT metabolism. Doses of PCPA that ameliorated the depression of LCGU in injured brain completely prevented increases in both 5-HT and its metabolite 5-hydroxyindoleacetic acid seen following traumatization in untreated animals. These results provide evidence that decreased LCGU in lesioned brain is due to an activation of the serotonergic system by traumatization. The data are in agreement with the postulated inhibitory role of serotonin in the cortex and its involvement in functional alterations associated with injury. They suggest that blockage of this neurotransmitter system may have a potential in the development of novel therapeutic approaches to brain injury.
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PMID:The effect of p-chlorophenylalanine on cerebral metabolism and biogenic amine content of traumatized brain. 245 25

Patients with Huntington's disease (HD) commonly have concomitant depressive disorders. Prompted by reports of elevated corticotropin releasing factor (CRF) and reduced 5-hydroxyindoleacetic acid (5-HIAA) concentrations in lumbar cerebrospinal fluid (CSF) of patients with major depression, these CSF constituents were examined in 56 nonmedicated patients who were in the early stages of HD. Elevated CRF concentrations were found in patients with HD in comparison with a control group of 21 subjects without neurologic illness. The CSF 5-HIAA concentrations in patients with HD did not differ from that in four normal volunteers. Patients with HD who had depressive disorders (major depression or dysthymia) did not differ from those without depression with respect to CSF 5-HIAA or CRF concentration. However, a positive correlation was observed between severity of major depression and CRF concentration. These findings suggest that the depression associated with HD may differ neurochemically from that seen in other major depressive disorders, and support the notion that clinically significant depressive symptoms reflect heterogeneous pathophysiologic conditions with different neurochemical correlates.
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PMID:Cerebrospinal fluid correlates of depression in Huntington's disease. 245 53


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