Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular and biochemical bases for interactions between the immune and central nervous systems are described. Immune cytokines not only activate immune function but also recruit central stress-responsive neurotransmitter systems in the modulation of the immune response and in the activation of behaviors that may be adaptive during injury or inflammation. Peripherally generated cytokines, such as interleukin-1, signal hypothalamic corticotropin-releasing hormone (CRH) neurons to activate pituitary-adrenal counter-regulation of inflammation through the potent antiinflammatory effects of glucocorticoids. Corticotropin-releasing hormone not only activates the pituitary-adrenal axis but also sets in motion a coordinated series of behavioral and physiologic responses, suggesting that the central nervous system may coordinate both behavioral and immunologic adaptation during stressful situations. The pathophysiologic perturbation of this feedback loop, through various mechanisms, results in the development of inflammatory syndromes, such as rheumatoid arthritis, and behavioral syndromes, such as depression. Thus, diseases characterized by both inflammatory and emotional disturbances may derive from common alterations in specific central nervous system pathways (for example, the CRH system). In addition, disruptions of this communication by genetic, infectious, toxic, or pharmacologic means can influence the susceptibility to disorders associated with both behavioral and inflammatory components and potentially alter their natural history. These concepts suggest that neuropharmacologic agents that stimulate hypothalamic CRH might potentially be adjunctive therapy for illnesses traditionally viewed as inflammatory or autoimmune.
 ...
PMID:The stress response and the regulation of inflammatory disease. 141 62

Advances in neuropeptide neurobiology in the last decade are illustrated by studies of corticotropin-releasing factor (CRF), the 41 amino acid-containing peptide that controls the anterior pituitary secretion of adrenocorticotropin and other pro-opiomelanocortin products. Corticotropin-releasing factor is synthesized in both hypothalamic and extrahypothalamic perikarya in a large prohormone form, (186 amino acids), then it is processed and transported to nerve terminals where it is released in its active form by a calcium-dependent mechanism. Corticotropin-releasing factor biosynthesis can now be measured by in situ hybridization because of the elucidation of the CRF gene sequence. Once released, CRF acts on high-affinity CRF receptors, and signal transduction is mediated by activation of adenylate cyclase in certain brain areas, and perhaps by phosphoinositide hydrolysis. In other brain areas CRF is inactivated by peptidases that degrade the hormone, though these are not well characterized. A CRF binding protein has been identified in plasma, and perhaps in brain. Considerable evidence exists from cerebrospinal fluid studies, postmortem tissue receptor measurements, and CRF stimulation test studies to support the hypothesis that CRF is hypersecreted in depression, resulting in both pituitary-adrenal axis hyperactivity and certain signs and symptoms of depression, e.g., decreased libido, insomnia, and decreased appetite. There is also evidence for an involvement of CRF in the pathophysiology of anxiety disorders and in the mechanism of action of benzodiazepines. The development of selective CRF-receptor antagonists will permit direct testing of the hypothesis that CRF hypersecretion is responsible for certain of the cardinal features of affective and anxiety disorders.
 ...
PMID:New vistas in neuropeptide research in neuropsychiatry: focus on corticotropin-releasing factor. 161 Apr 87

In this study, we have measured the following biological variables in 78 depressed inpatients: adrenocorticotrophic hormone (ACTH) responses to corticotropin releasing factor (CRH: 100 micrograms intravenously), postdexamethasone cortisol and ACTH values, and circulating concentrations of L-tryptophan (L-TRP). Patients were categorized according to the DMS-III as (1) minor depression, (2) simple major depression, and (3) major depression with melancholia/psychotic features. By means of various pattern recognition methods, we determined whether these diagnostic groups constitute discrete biological classes or form relevant stages (i.e., continuous categories) in a continuum of progressing biological dysfunction. We established that unipolar depression constitutes one biological continuum characterized by a progression of lower CRH-induced ACTH responses, lower L-TRP levels, and higher postdexamethasone cortisol and ACTH values along the diagnostic spectrum. However, the biological differences in these markers between melancholia and minor depression are quantitatively prominent to the extent that they become qualitative. These findings support the biological heterogeneity hypothesis of melancholia. Simple major depression is a heterogeneous class with regard to the biological markers employed.
 ...
PMID:Biological heterogeneity of melancholia: results of pattern recognition methods. 165 16

Because diazepam binding inhibitor (DBI) and its processing products coexist with gamma-aminobutyric acid (GABA) in several axon terminals, DBI immunoreactivity was measured in the cerebrospinal fluid (CSF) of individuals suffering from various neuropsychiatric disorders, that are believe to be associated with abnormalities of GABAergic transmission. Increased amounts of DBI-like immunoreactivity were found in the CSF of patients suffering from severe depression with a severe anxiety component (Barbaccia, Costa, Ferrero, Guidotti, Roy, Sunderland, Pickar, Paul and Goodwin, 1986). Moreover, the amount of DBI and its processing products was found to be increased in the CSF of patients with hepatic encephalopathy (HE) (Rothstein, McKhann, Guarneri, Barbaccia, Guidotti and Costa, 1989; Guarneri, Berkovich, Guidotti and Costa, 1990). The clinical rating of HE correlated with the extent of the increase in DBI in CSF. Other lines of research suggest that DBI and DBI processing products may be important factors in behavioral adaptation to stress, acting via benzodiazepine (BZD) binding sites, located on mitochondria. DBI and its processing products, ODN and TTN, are present in high concentrations in the hypothalamus and in the amygdala, two areas of the brain that are important in regulating behavioral patterns associated with conflict situations, anxiety and stress. In CSF, the content of DBI changes in association with corticotropin releasing factor (CRF) (Roy, Pickar, Gold, Barbaccia, Guidotti, Costa and Linnoila, 1989). Finally DBI is preferentially concentrated in steroidogenic tissues and cells (adrenal cortical cells, Leydig cells of the testes and glial cells of the brain).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Role of DBI in brain and its posttranslational processing products in normal and abnormal behavior. 166 69

Corticotropin-releasing factor (CRF) has been implicated as a neurotransmitter in the noradrenergic nucleus, locus coeruleus (LC), and is thought to be hypersecreted in depression. Therefore, the hypothesis that antidepressants interfere with CRF neurotransmission in the LC was tested. The acute and chronic effects of desmethylimipramine (DMI), sertraline (SER), phenelzine (PHE), mianserin (MIA), and cocaine (COC) were quantified on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by intracerebroventricular (i.c.v.)-administered CRF, and LC activation by stress in halothane-anesthetized rats. No consistent effect of the drugs on LC spontaneous discharge rate or sensory responsiveness was observed after acute administration. LC spontaneous discharge rates in rats chronically administered the drugs were similar to rates recorded in matched controls, with the exception of PHE and COC. In these rats, LC spontaneous discharge rates were lower than those of untreated rats. Interestingly, LC responses to repeated sciatic nerve stimulation (as measured by the ratio of evoked-to-tonic LC discharge rate) were enhanced in rats chronically administered SER and PHE. This is opposite to the reported effects of i.c.v.-administered CRF. This was not observed with chronic administration of DMI, MIA, or COC. The most striking effect associated with chronic administration of DMI and MIA was the attenuation of LC activation by hemodynamic stress. Because this activation requires CRF release in the LC region, and because none of the antidepressants altered LC activation by i.c.v.-administered CRF, the data suggest that chronic administration of either antidepressant, DMI or MIA, results in attenuation of stress-elicited CRF release in the LC.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Antidepressant interactions with corticotropin-releasing factor in the noradrenergic nucleus locus coeruleus. 177 96

Neuroendocrine and catecholamine dysfunctions in depression may be linked by corticotropin-releasing factor (CRF) effects on locus coeruleus (LC) neurons. One consequence of CRF hypersecretion in depression would be persistent elevated levels of LC discharge and diminished responses to phasic sensory stimuli. The hypothesis that antidepressants could reverse these changes was tested by characterizing effects of pharmacologically distinct antidepressants on LC sensory-evoked discharge, LC activation by stress, and LC activation by CRF. The most consistent effect of all of the antidepressants tested was a decrease in LC sensory-evoked discharge after acute administration. However, tolerance occurs to these effects after chronic administration. With chronic administration each of the antidepressants produced effects which could potentially interfere with CRF function in the LC. Desmethylimipramine and mianserin attenuated LC activation by a stressor which requires endogenous CRF, suggesting that these antidepressants attenuate stress-elicited release of CRF and perhaps the hypersecretion that occurs in depression. The serotonin reuptake inhibitor, sertraline (SER), enhanced the signal-to-noise ratio of the LC sensory response, an effect opposite to that of CRF. Thus, SER could serve as a functional antagonist of CRF that is hypersecreted in depression. The finding that three pharmacologically distinct antidepressants share the potential to interfere with CRF function in the LC implies that this may be an important common mechanism for antidepressant activity.
 ...
PMID:Pharmacology of locus coeruleus spontaneous and sensory-evoked activity. 181 24

A number of studies have shown significant interactions between neuronal systems involved with corticotropin-releasing factor (CRF) and either the clinical manifestations of depression and anxiety or the effects of antidepressant or anxiolytic drugs. In the present study, effects of CRF were studied alone and in combination with imipramine and with the sedative-hypnotic/anxiolytic drugs pentobarbital and chlordiazepoxide. Interactions of CRF with the novel, atypical anxiolytic buspirone were also examined. Interactions were evaluated through the use of schedule-controlled responding, responding suppressed by punishment, and drug discrimination procedures using the conditioned key-pecking response of pigeons. Effects of CRF were significantly enhanced when given in combination with imipramine with low noneffective imipramine doses potentiating the rate-reducing effects of CRF. Similarly, in pigeons trained to discriminate imipramine from saline, noneffective doses of CRF shifted the imipramine dose-response curve more than twofold to the left. Low doses of imipramine that produced saline key responding, produced imipramine-key responding when coadministered with CRF. The CRF antagonist alpha-helical CRF9-41 did not alter the rate-decreasing effects of imipramine. Effects of CRF on schedule-controlled responding were, however, antagonized by the administration of chlordiazepoxide and pentobarbital but not by buspirone, suggesting that CRF interacts with the GABA/benzodiazepine receptor mechanism complex but not with those systems involved in mediating the effects of buspirone. These results suggest that CRF interacts in significant ways with specific neurotransmitter systems subserving depression and anxiety.
 ...
PMID:Interactions of corticotropin-releasing factor with antidepressant and anxiolytic drugs: behavioral studies with pigeons. 197 Jul 44

Corticotropin-releasing factor (CRF), which may serve as a neurotransmitter in the noradrenergic nucleus, locus coeruleus (LC), has been postulated to be hypersecreted in depression. The present study was designed to test the hypothesis that antidepressants interfere with CRF putative neurotransmission in the LC. The acute and chronic effects of the atypical antidepressant mianserin on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by a stressor which requires endogenous CRF, and LC activation by ICV CRF were characterized in halothane-anesthetized rats. Acute IV administration of mianserin (0.0001-1.0 mg/kg) increased LC spontaneous discharge and decreased LC discharge evoked by repeated sciatic nerve stimulation in a dose-dependent manner. Additionally, mianserin (0.1 mg/kg) inhibited LC activation by hemodynamic stress (IV infusion of nitroprusside) and by ICV administration of CRF (3.0 micrograms). In rats chronically administered mianserin LC spontaneous and sensory-evoked discharge rates, and LC activation by CRF were similar to those of untreated rats or rats chronically administered saline. Moreover, acute IV administration of mianserin (0.1 mg/kg) to rats chronically treated with mianserin was less effective in altering LC spontaneous and sensory-evoked discharge. In contrast, LC activation by hemodynamic stress was still greatly attenuated in rats chronically administered mianserin. This is similar to the previously reported effect produced by chronic administration of the antidepressant, desmethylimipramine. The present results demonstrate that acute administration of low doses of mianserin attenuates LC activation by a variety of stimuli and suggest that tolerance develops with chronic administration to some of the effects of mianserin on LC discharge characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Acute and chronic effects of the atypical antidepressant, mianserin on brain noradrenergic neurons. 205 37

Studies in depression using a maximal stimulatory dose of corticotropin releasing factor have concluded that elevated resting cortisol levels in depressed patients exert a negative feedback effect on the corticotroph, resulting in a decreased corticotropin response. In this preliminary report, we examine the effects of a submaximal dose of corticotropin releasing factor on the release of another corticotroph secretory product, beta-lipotropin-beta-endorphin. We observed a decreased beta-lipotropin-beta-endorphin response in depressed subjects, but a normal adrenal cortisol response. Although the total beta-lipotropin-beta-endorphin response was decreased, the initial secretory response did not differ between patients and normal controls. Rather, the patients appeared to turn off secretion faster. This rapid shutoff was seen in all patients regardless of resting cortisol levels, suggesting that resting cortisol levels alone do not explain the decreased response seen in depressed patients.
 ...
PMID:Beta-lipotropin-beta-endorphin response to low-dose ovine corticotropin releasing factor in endogenous depression. Preliminary studies. 213 63

Corticotropin-releasing factor (CRF), the hormone responsible for adrenocorticotropin release during stress, is thought to be hypersecreted in depression. Because recent studies suggest that CRF may serve as a neurotransmitter in the major noradrenergic nucleus, locus coeruleus (LC), it was hypothesized that antidepressants interfere with the putative neurotransmitter role of CRF in the LC by either: 1) decreasing release of CRF; 2) pharmacologically antagonizing CRF; or 3) functionally antagonizing CRF by producing effects on LC cells that oppose these of CRF. In order to test this hypothesis, the effects of acute and chronic administration of two antidepressants, a norepinephrine re-uptake inhibitor (desmethylimipramine, DMI) and a serotonin re-uptake inhibitor (sertraline, SER), on LC spontaneous discharge, LC sensory evoked discharge, LC activation by a stressor and LC activation by CRF, were compared in halothane-anesthetized rats. Acute i.v. administration of DMI decreased both LC spontaneous discharge and discharge evoked by repeated sciatic nerve stimulation. In contrast, acute i.v. SER administration decreased only evoked LC discharge rate. Chronic DMI administration (10.0 mg/kg/day, i.p., 21 days) resulted in tolerance to its effects on spontaneous and sensory-evoked LC discharge. However, chronic DMI administration attenuated LC activation by hemodynamic stress, which is thought to require CRF release. LC activation by intracerebroventricular CRF was not altered in the chronic DMI rats. In contrast to DMI, chronic SER (10 mg/kg/day, i.p., 21 days) did not alter LC activation by either stress of CRF. However, the response of LC cells to repeated sciatic nerve stimulation was somewhat enhanced in chronic SER rats. This is an effect that is opposite that produced by CRF.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Antidepressant actions on brain noradrenergic neurons. 233 58


1 2 3 4 5 6 7 8 9 10 Next >>