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 normal hearts, endothelin-1 (ET-1) has been shown to initiate myocyte growth and to modulate cardiac function. However, regulation of the various components of the system and the functional effects of ET-1 in established left ventricular hypertrophy (LVH) are less clear. We thus studied ET-1, ET(A) receptor, and endothelin converting enzyme (ECE-1) mRNA regulation as well as the effects of ET-1 on coronary resistance, LV contractility and relaxation in hypertrophied rat hearts. Cardiac pressure overload, secondary to banding of the ascending aorta, resulted in a transient increase of cardiac ET-1 and ET(A) receptor mRNAs that reached a maximum at 2 days (+75% and +40%, respectively, P<0.05, each). ET-1 mRNA levels reached a second peak at 84 days of pressure overload (+60%, P<0.05), at the later time point in conjunction with elevated ECE-1 mRNA levels (+20%, P<0.05). The functional implications of ET-1 were examined in a study of isolated perfused hearts. Both hearts with established LVH and sham control hearts responded to ET-1 perfusion (10(-1)] to 10(-9) M) with an increase of coronary perfusion pressure (CPP; +85+/-15 and +75+/-8 mm Hg; P<0.001 each) and a slight decrease of LV systolic pressure (LVP; -12+/-9 and -9+/-7 mm Hg; P = NS). In contrast, ET-1 increased LV end-diastolic pressure (LVEDP) only in LVH hearts (+22+/-7 mm Hg, P<0.05 versus baseline and +20+/-7 mm Hg, P<0.05 versus sham). Direct stimulation of protein kinase C mimicked the effects of ET-1, whereas inhibition of this kinase or the Na+ -H+ exchanger blunted the effects of ET-1 on CPP, LVP, and LVEDP. Interestingly, coadministration of the vasodilator and the nitric oxide (NO) donor nitroglycerin not only prevented the increase of CPP and LVEDP, but also uncovered a slight positive inotropic effect of ET-1 in LVH hearts. Thus, the cardiac expression of ET-1, ET(A), and ECE-1 mRNAs displays a distinct pattern during early and advanced cardiac pressure overload. Furthermore, ET-1 mediates a slight depression of systolic, and a profound depression of diastolic, functional parameters in hearts with established LVH, effects that appear to be secondary to ET-1-related coronary vasoconstriction. The data suggest a functional role of the endothelin system in hearts with established pressure overload hypertrophy.
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PMID:The cardiac endothelin system in established pressure overload left ventricular hypertrophy. 1054 94

There are a few reports of side-effects of LHRHa treatment in childhood, the mechanisms of which remain little understood. Such effects can be local reactions: erythema, induration, wheal and sterile abscess formation, which can be possible causes of therapy failure. There are negative effects on growth velocity and final height requiring rhGH therapy or a suppressive treatment when bone age >13 years. Excessive weight gain can occur by various mechanisms: menopausal-like phenomena, or LHRHa influence on hypothalamic and/or leptin-mediated control of body weight. Other possible adverse effects involve increased ovarian volume with possible POS development; however, there is no evidence correlating LHRHa, hyperandrogenism and POS. The latter appears related to CPP onset with pre-existing hyperandrogenism, although lengthier follow-up is necessary to confirm this. Bone density decreases during therapy, but final peak bone mass is in the normal range. Frequent transitory side-effects include headaches, hot flushes, depression and irregular menses.
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PMID:Side effects of GnRH analogue treatment in childhood. 1096 24

Spreading depression (SD) as well as hypoxia-induced SD-like depolarization in forebrain gray matter are characterized by near complete depolarization of neurons. The biophysical mechanism of the depolarization is not known. Earlier we reported that simultaneous pharmacological blockade of all known major Na(+) and Ca(2+) channels prevents hypoxic SD. We now recorded extracellular voltage, Na(+), and K(+) concentrations and the intracellular potential of individual CA1 pyramidal neurons during hypoxia of rat hippocampal tissue slices after substituting Na(+) in the bath by an impermeant cation, or in the presence of channel blocking drugs applied individually and in combination. Reducing extracellular Na(+) concentration [Na(+)](o) to 90 mM postponed the hypoxia-induced extracellular DC-potential deflection (DeltaV(o)) and reduced its amplitude, and it also postponed the SD-like depolarization of neurons. After lowering [Na(+)](o) to 25 mM, SD-like DeltaV(o) became very small, indicating that an influx of Na(+) is required for SD; influx of Ca(2+) ions alone is not sufficient. We then asked whether the SD-related Na(+) current flows through glutamate-controlled and/or through voltage-gated Na(+) channels. Administration of either the non-N-methyl-D-aspartate (NMDA) receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), or the NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) postponed the hypoxic DeltaV(o) and depressed its amplitude but the effect of the combined administration of these two drugs was not greater than that of either alone. During the early phase of hypoxia, before SD onset, [K(+)](o) increased faster and reached a much higher level in the presence of glutamate antagonists than in their absence. The [K(+)](o) level reached at the height of hypoxic SD was, however, not affected. When TTX was added to DNQX and CPP, SD was prevented in half the trials. When SD did occur, it was greatly delayed, yet eventually neurons depolarized to the same extent as in normal solution. The SD-related sudden drop in [Na(+)](o) was depressed by only 19% in the presence of the three drugs, indicating that Na(+) can flow into cells through pathways other than ionotropic glutamate receptors and TTX-sensitive Na(+) channels. We conclude that, when they are functional, glutamate-receptor-mediated and voltage-gated Na(+) currents are the major generators of the self-regenerative rapid depolarization, but in their absence other pathways can sometimes take their place. The final level of SD-like depolarization is determined by positive feedback and not by the number of channels available. A schematic flow chart of the events generating hypoxic SD is discussed.
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PMID:Na(+) dependence and the role of glutamate receptors and Na(+) channels in ion fluxes during hypoxia of rat hippocampal slices. 1102 79

We investigated the effect of cholesterol on serotonergic receptor function in 20 healthy male and 10 healthy female subjects using cortisol responses to meta-chlorophenylpiperazine (m-CPP) neuroendocrine challenge tests. M-CPP, a metabolite of the antidepressant trazodone, has been widely used in psychopharmacology research as a probe of serotonin function. In the human brain, m-CPP binds both to various serotonergic receptors, mainly 5-HT(2C), and to alpha(2)-adrenoceptors. After an overnight fast, the subjects received m-CPP (0.5 mg/kg) or identical placebo capsules orally in a randomized, double blind, crossover design. Blood was obtained for measurement of cholesterol and cortisol. In some analyses, especially in males, there were significant positive correlations between serum cholesterol levels and cortisol responses. These findings suggest the possibility that serum cholesterol levels may be positively associated with serotonergic receptor function. The existence of such an association may provide an explanation for reported increases in depression, suicide and violence in individuals with low or lowered cholesterol.
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PMID:Relationship between serum cholesterol levels and meta-chlorophenylpiperazine-induced cortisol responses in healthy men and women. 1106 89

The Fawn-Hooded (FH) rat strain, with well-documented changes in their serotonergic and noradrenergic systems, is a putative genetic model for some neuropsychiatric disorders like depression, alcohol abuse, and anxiety. Because social phobia frequently occurs in combination with these disorders and there are no social anxiety-related data in FH rats in the literature, we measured the behavior of FH rats in the social interaction test. In addition, the effects of the anxiogenic Serotonin-2C (5-HT2C) receptor agonist, m-chlorophenylpiperazine (m-CPP), were studied. Male FH, Wistar (W), and Sprague-Dawley (SD) rats were used in two different test conditions of the social interaction test: the high light, unfamiliar arena, associated with high anxiety, and the low light, familiar arena, associated with low anxiety-like behavior. All social behaviors were markedly diminished in FH rats that suggested higher anxiety in these animals. Total social interaction time was reduced by 60-70% in FH rats compared either to W or SD rats under high light, unfamiliar or low light, familiar conditions, respectively. Aggressive behavior was reduced at least by 85% in FH rats. Locomotor activity and exploratory behavior were only minimally, in most comparisons, not significantly affected in FH rats. Total social interaction time, aggression, and locomotor activity were decreased, and self-grooming increased by m-CPP (0.5 mg/kg, ip) in all three strains. m-CPP decreased total social interaction time thus, caused anxiety most efficiently in FH rats (reduced by 69%, 50%, and 55% in FH, W, and SD rats, respectively), but other effects of the drug were similar in the three strains. Our studies provide evidence that the FH rat strain may be a genetic model of social phobia or other anxiety disorders with impaired social behavior.
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PMID:High social anxiety and low aggression in Fawn-Hooded rats. 1123 74

Fifteen patients with major depression, dysthymia, or anxiety disorder with depressed mood (DSM-IV diagnoses) and 16 controls received single oral doses of 0.5mg/kg metachlorophenylpiperazine (m-CPP), a 5-HT(2C) agonist, and 10 mg ipsapirone, a 5-HT(1A) agonist, according to double-blind, placebo-controlled, cross-over design. The groups' levels of cortisol, adrenocorticotrophic hormone (ACTH) and prolactin did not differ at baseline. Both 5-HT agonists significantly elevated cortisol, ACTH, and prolactin. The cortisol response to ipsapirone was significantly blunted in major depression and dysthymia patients. Neuroendocrine responses to m-CPP did not differ between groups, but m-CPP selectively increased profile of mood states (POMS) depression and tenseness scores in patients. No effects of ipsapirone on mood were found. However, ipsapirone impaired memory performance in controls, but tended to improve memory performance in patients. The results support the evidence for both hypothalamic and possibly hippocampal 5-HT(1A) receptor desensitisation and non-hypothalamic, 5-HT(2C) receptor sensitisation, probably fronto-cortical, in patients with major depression and dysthymia.
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PMID:Dissociable hormonal, cognitive and mood responses to neuroendocrine challenge: evidence for receptor-specific serotonergic dysregulation in depressed mood. 1264 46

Hypercortisolism and altered serotonergic function may account for the pathological symptoms seen in depression. This study examines the impact of 4 days continuous corticosterone treatment on 5-HT agonist-induced behaviour to delineate changes in 5-HT receptor function in the adult rat. The flat body posture, reciprocal forepaw treading, elevated corticosterone, hyperglycaemia, hypothermia and reduced hippocampal 5-HT induced by the 5-HT(1A) agonist 8-OHDPAT (0.3 mg/kg ip) were all significantly attenuated by the corticosterone implant. The elevation in plasma corticosterone and back muscle contractions evoked by the 5-HT(2A) agonist DOI (1 mg/kg ip) were attenuated, whilst wet-dog shakes were enhanced by corticosterone treatment. 5-HT(2B) agonist-induced behaviour and the hypolocomotion and hypophagia induced by the 5-HT(2C) agonist m-CPP (2.5 mg/kg ip) were unaltered but the mCPP-induced elevation in corticosterone was abolished by corticosterone treatment. Hypothalamic 5-HT receptors mediating corticosterone- and 5-HT(1A) receptors, whether on serotonergic nerve terminals or postsynaptic neurones, were downregulated by corticosterone treatment. In contrast, 5-HT(2A) receptors may be up- or downregulated dependent on whether they are on supraspinal or spinal neurones, respectively. A comparison of the brain region-dependent alteration in serotonergic function produced by hypercorticosterone in the rat with that seen in depression is discussed.
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PMID:Alteration in 5-hydroxytryptamine agonist-induced behaviour following a corticosterone implant in adult rats. 1188 72

Relationships between plasma concentrations of trazodone and m-chlorophenylpiperazine (m-CPP) and the clinical effects were studied in 26 patients (12 males and 14 females) with major depression during three weeks' treatment of 150 mg/d trazodone using an open-study design. Depressive symptoms were evaluated by Montgomery Asberg Depression Rating Scale (MADRS), and subjective side effects were assessed by UKU side effects rating scale (UKU) before treatment and at weekly intervals. Plasma concentrations of trazodone and m-CPP were measured by HPLC. There were significant linear relationships between the steady-state plasma concentration (Css) of trazodone and both the final MADRS score (rs = -0.529, P < 0.01) and the percent improvement at 3 weeks (r = 0.442, P < 0.05). Moreover, the proportion of responders (a final MADRS score of 10 or less) was significantly higher in the group with a trazodone concentration greater than 714 ng/mL (6/8 vs 3/18, P = 0.008). No significant correlation was found between UKU score and the Css for either compound nor between the UKU score and the ratio of m-CPP/trazodone. The current study suggests that a therapeutic response is dependent on the plasma concentration of trazodone but not m-CPP and that a plasma trazodone concentration of about 700 ng/mL may be a threshold for a good therapeutic response.
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PMID:Relationship between plasma concentrations of trazodone and its active metabolite, m-chlorophenylpiperazine, and its clinical effect in depressed patients. 1214 43

The role of NMDA mechanisms in spinal pathways mediating acute nociceptive input to the somatosensory cortex is not clear. In this study, the effect of NMDA-antagonists on nociceptive C fibre transmission to the primary somatosensory cortex (SI) was investigated. Cortical field potentials evoked by CO(2)-laser stimulation of the skin were recorded in the halothane/nitrous oxide anaesthetized rat. The SI nociceptive evoked potential (EP) amplitudes were dependent on the frequency of noxious heat stimulation. The amplitudes of SI potentials evoked by CO(2)-laser pulses (duration 15-20 ms, stimulation energy 21-28 mJ/mm(2)) delivered at a frequency of 0.1 Hz were approximately 40% of the amplitudes of potentials evoked by 1.0 Hz stimulation. After intrathecal lumbar application of either of the NMDA-antagonists CPP or MK-801, the amplitudes of nociceptive SI potentials, evoked by 1.0 Hz stimulation of the contralateral hindpaw, were reduced to approximately 40% of controls. By contrast, field potentials evoked by 0.1 Hz stimulation of the hindpaw were unaffected by MK-801. SI potentials evoked by 1.0 Hz stimulation of the contralateral forepaw did not change after lumbar application of CPP or MK-801, indicating that the depression of hindpaw EPs was due to a segmental effect in the spinal cord. It is concluded that spinal NMDA-receptor mechanisms amplify the acute transmission of nociceptive C fiber input to SI in a frequency-dependent way.
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PMID:Spinal NMDA-receptor dependent amplification of nociceptive transmission to rat primary somatosensory cortex (SI). 1285 29

Previous in vitro studies demonstrated that long-term potentiation (LTP) could be elicited at medial perforant path (MPP) synapses onto hippocampal granule cells in slices from 7-day-old rats. In contrast, in vivo studies suggested that LTP at perforant path synapses could not be induced until at least days 9 or 10 and then in only a small percentage of animals. Because several characteristics of the oldest granule cells are adult-like on day 7, we re-examined the possibility of eliciting LTP in 7-day-old rats in vivo. We also recorded from 8- and 9-day-old rats to further elucidate the occurrence and magnitude of LTP in neonates. With halothane anesthesia, all animals in each age group exhibited synaptic plasticity of the excitatory postsynaptic potential following high-frequency stimulation of the MPP. In 7-day-old rats, LTP was elicited in 40% of the animals and had an average magnitude of 143%. Long-term depression (LTD) alone (magnitude of 84%) was induced in 40% of the animals, while short-term potentiation (STP) alone (magnitude of 123%) was induced in 10%. STP followed by LTD was elicited in the remaining 10%. Data were similar for all ages combined. In addition, the N-methyl-d-aspartate (NMDA) antagonist (R,S)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked the occurrence of LTP at each age and doubled the percentage of animals expressing LTD alone for all ages combined. These results demonstrate that tetanic stimulation can elicit LTP or LTD at MPP synapses in 7-day-old rats, supporting our premise that at least a portion of the dentate gyrus is functional at this early age.
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PMID:In vivo recordings of long-term potentiation and long-term depression in the dentate gyrus of the neonatal rat. 1464 75


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