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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The classical norepinephrine (NE) and serotonin (5-HT) theories of depression have been abandoned in light of recent chronic antidepressant drug studies. 2. The new NE and 5-HT theories of depression focus on the dynamics of receptor subtypes in depression and chronic antidepressant treatments. 3. Recent studies in molecular genetics suggest a reclassification of monoamine receptors based on receptor structural homologies in DNA and amino acid sequences rather than receptor affinity for ligands. 4. Electrophysiologic studies in rats suggest that 5-HT1 receptor function is facilitated by chronic antidepressant treatment. 5. Preclinical studies employing a range of 5-HT1 mediated behavioral models also suggest that chronic antidepressant treatment facilitates transmission at central 5-HT1 receptors. 6. Patient studies, employing a 5-HT1 mediated neuroendocrine model, suggest that depression is associated with decreased transmission at CNS 5-HT1 receptors; and that chronic antidepressant treatment facilitates 5-HT1 receptor responsiveness in depressed patients. 7. New 5-HT1 selective agonists have been developed and found to be clinically effective antidepressants. 8. The above clinical and preclinical data suggest that some forms of depression are related to a decreased responsiveness of 5-HT1 receptors which is reversed by chronic antidepressant treatment. 9. Beta adrenergic and NE-stimulated cyclic AMP studies suggest that chronic antidepressant treatment decreases the responsiveness of central beta-adrenergic receptors, particularly beta-1 receptors. 10. A novel approach to antidepressant drug development focuses on identifying centrally active beta-1 agonists, which like clinically proven antidepressants, decrease beta-1 receptor responsiveness with chronic treatment. 11. 5-HT2 receptor binding studies and initial studies of 5-HT2 receptor coupled PI turnover suggest that chronic antidepressant treatment decreases 5-HT2 receptor number and function. 12. The development of new atypical antidepressants with 5-HT2 receptor related mechanisms of action suggest that 5-HT2 receptors may be associated with certain types of depression and their clinical treatment.
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PMID:Depression and antidepressant therapy: receptor dynamics. 217 22

We have previously demonstrated that induction of the heat-shock response in rats results in improved recovery of isolated Langendorff-perfused rat hearts subjected to low-flow ischemia followed by reperfusion (Currie et al., 1988). The mechanisms underlying this protective effect of heat-shock are uncertain although the protection was associated with enhanced content of the antioxidant enzyme catalase but not superoxide dismutase or glutathione peroxidase (Currie et al., 1988). Various investigators have suggested the importance of improved energy metabolism in determining recovery following ischemia (Pasque and Wechsler, 1984; Haas et al., 1984; Devous and Lewandowski, 1987). We therefore examined, using a working rat heart model subjected to 10 or 15 min zero flow ischemia whether changes in energy metabolites could account for the protective effect of the heat-shock response. Hearts perfused 24 h after induction of heat-shock failed to demonstrate significant improvement of recovery following 10 min ischemia, however recovery was significantly enhanced in hearts reperfused after 15 min ischemia. Ischemia produced a depression in both ATP and creatine phosphate (CP) content whereas a moderate elevation in ADP and AMP and a marked increase in tissue lactate were evident. These changes were unaffected by prior heat-shock treatment. For both durations of ischemia tissue metabolites were determined during early (5 min) and late (30 min) reperfusion. Although partial recovery in high energy phosphates and a return of ADP, AMP and lactate to near-normal levels were evident, no differences in energy products were observed between hearts from normal or heat-shocked animals, in spite of significantly enhanced recovery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Improved post-ischemic ventricular recovery in the absence of changes in energy metabolism in working rat hearts following heat-shock. 223 33

A limited occipital craniotomy was conducted on urethane-anesthetized, spontaneously breathing rats to expose the caudal medulla in the region of the obex. Microinjections of 5'-N-ethylcarboxamidoadenosine (NECA), an adenosine analog, were made into the medial region of the caudal nucleus tractus solitarius (NTS) at the level of the caudal tip of the area postrema, an area of the NTS in which there is known to be a functional co-existence of cardiovascular and respiratory-related neuronal elements. Cardiorespiratory responses were subsequently recorded for a 60 min test period. Microinjections of NECA, in the dose range of 0.35-350 pmol per rat, produced significant dose-related reductions in respiratory rate which were accompanied by dose-dependent increases in tidal volume and these pronounced effects on respiration persisted throughout the test period. In contrast, the effects of NECA microinjections on cardiovascular parameters in this region of the NTS were bidirectional and elicited considerably more complex responses during the test period. During the initial period (2-5 min) following injection, NECA elicited significant hypotension (at lower doses) and pressor responses (at higher doses) in addition to significant bradycardia (at lower doses) whereas by the end of the 60 min test period, almost all doses of NECA had resulted in hypertension and tachycardia. Multivariate analysis of variance (MANOVA) and correlation statistics indicated that the effects of NECA on blood pressure during the initial 2-5 min were dose-dependent and unlikely related to depression of respiratory frequency. A further examination of the data by MANOVA indicated that the pharmacological effects of NECA during the 60 min test period exhibited a highly significant and specific dose-dependent and time-related response pattern for the respiratory, but not the cardiovascular, parameters. Taken together, these manifold response patterns suggest that the respiratory effects of NECA may be mediated by different intrinsic mechanisms in the NTS than are the cardiovascular effects of NECA. At the end of the 60 min test period following the administration of NECA, the respiratory rate remained profoundly depressed. In view of previous studies showing that microinjections of cyclic AMP analogs, forskolin, isoproterenol and adenosine into the same NTS sites elicit a similar depression of respiration, the results with NECA in the present study further support the notion that cyclic AMP may serve as a second messenger in NTS respiratory control regions and these respiratory depressant effects may be mediated by a single adenosine receptor subtype.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cardiorespiratory function is altered by picomole injections of 5'-N-ethylcarboxamidoadenosine into the nucleus tractus solitarius of rats. 233 63

The effects of G1 phase growth arrest on purine biosynthesis were studied in cultured S49 T lymphoma cells. Incubations of wildtype S49 cells for 18 hr with dibutyryl cyclic AMP or forskolin, two agents which induced G1 arrest, reduced the rates of purine biosynthesis by 95%. Time course and concentration dependence studies indicated that the decrease in rates of purine biosynthesis correlated with the extent of G1 phase arrest. Similar studies with somatic cell mutants deficient in some component of cyclic AMP action or metabolism indicated that the depression in purine synthetic rates required G1 arrest and did not result from cell death. Rates of RNA and DNA synthesis were also markedly diminished in the growth arrested cells. Measurements of purine rates in the presence of azaserine indicated that the block in purine biosynthesis was prior to the formation of phosphoribosylformylglycinamide. Additionally, the activities of adenylosuccinate synthetase and IMP dehydrogenase were diminished in G1 arrested cells. The levels of all controlling enzymes, substrates, and cofactors, however, were not diminished in G1 arrested cells. Despite diminished rates of purine biosynthesis, the amounts of intracellular nucleotides in G1 cells were equivalent to those in exponentially growing cells. However, the concentrations of intracellular nucleotides were 30-50% higher in the growth arrested cells. These results suggested that perturbations in the consumption of nucleotides via inhibition of nucleic acid synthesis have profound effects on the purine pathway and indicated the importance of feedback inhibition by nucleotides in the regulation of purine synthesis in situ.
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PMID:Regulation of purine biosynthesis in G1 phase-arrested mammalian cells. 241 5

Using internally dialyzed neurons of Helix, we have examined the effects of sodium-pump activity and intracellular ATP concentration on transmembrane currents induced by acetylcholine (ACh) and gamma-aminobutyric acid (GABA). We also report on the effects of pump activity and levels of intracellular ATP on binding by Helix ganglia of 3H-alpha-bungarotoxin (3H-alpha-BT) and 3H-GABA. Both ouabain-containing and potassium-free solutions depressed the neurotransmitter-induced transmembrane current of one type of dialyzed neurons. An increase in the intracellular ATP concentration led to a depression of ACh-induced currents and to the disappearance of the blocking effect of ouabain on these currents. Intracellular ADP had a similar but smaller effect on transmitter-induced currents, and intracellular AMP was ineffective. The depressing effect of internal ATP on ACh-induced currents was absent in the presence of an inhibitor of membrane phosphorylation (dinitrophenol). The binding of tritium-labeled alpha-BT and GABA to the membranes was depressed by both ouabain-containing and K-free solutions and also by compounds (theophylline and NaF) which increase the levels of intracellular ATP. The results suggest that the Na pump modulates the affinity of ACh and GABA membrane receptors by the regulation of the phosphorylated state of membrane receptors.
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PMID:Further study of the correlation between Na-pump activity and membrane chemosensitivity. 241 57

The positive inotropic effects of the bipyridine derivatives amrinone and milrinone and of the benzimidazole compounds sulmazole, pimobendane, and UD-CG 212 Cl are due at least in part to inhibition of cardiac phosphodiesterase activity and hence to an increase in myocardial cyclic AMP (cAMP) content. Compared with the other agents, the contribution of the cAMP system appears to be relatively small in the case of pimobendane and UD-CG 212 Cl. This reduced effect is probably advantageous because an increase in cAMP leads not only to positive inotropic but also to positive chronotropic effects and possibly to arrhythmogenesis. The latter in particular may limit the usefulness of new cardiotonic agents, although--at least theoretically--a cAMP-dependent arrhythmogenic action might be overcome by additional "antiarrhythmic" properties, e.g., prolongation of the action potential, depression of transient depolarizations, or depression of the fast Na+ inward current. Sulmazole and pimobendane have been shown to have an additional effect on the contractile properties in that they increase the sensitivity of the myofibrils to Ca++.
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PMID:Phosphodiesterase-inhibiting properties of newer inotropic agents. 241 48

We attempted to determine whether there is a possible link between the effect of papaverine on p-aminohippurate (PAH) accumulation, on cyclic nucleotide content and on certain other cellular functional parameters in rat kidney cortical slices in vitro. Papaverine at a concentration of 0.1 mM almost completely inhibited PAH accumulation in the slices. However, cyclic guanosine 3', 5'-monophosphate (cyclic GMP) and cyclic adenosine 3', 5'-monophosphate (cyclic AMP) levels in the slices were not significantly affected by papaverine at 0.1 mM, though papaverine at a concentration of 1 mM increased the cyclic GMP level without affecting the cyclic AMP level. Papaverine (0.1 mM) produced a decrease in the sodium gradient and in the adenosine triphosphate (ATP) level in the slices. Calcium uptake by mitochondria, isolated from kidney cortex, was apparently decreased in the presence of 0.1 mM papaverine. These results suggest that the inhibition of phosphodiesterase probably does not explain the action of papaverine on PAH accumulation in the slices. The inhibition of PAH accumulation by papaverine is partly a reflection of the fall in the sodium gradient in the slices treated with papaverine. In addition, a depression of ATP level in the slices and an inhibition of mitochondrial calcium uptake may be related to a possible mechanism of action of papaverine on PAH accumulation.
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PMID:Influence of papaverine on cyclic nucleotide level and cellular metabolism in rat kidney cortex in terms of its inhibitory effect on p-aminohippurate transport. 242 72

1. Actions of the neuropeptide FMRFamide (Phe-Met-Arg-Phe-NH2) and its derivative YGG-FMRFamide (Tyr-Gly-Gly-Phe-Met-Arg-Phe-NH2) on Ca2+ current were examined in identified, voltage-clamped neurones in the abdominal ganglion of Aplysia californica. 2. 'Puffed' application of either peptide at concentrations of 1-50 microM was followed by a transient partial suppression of pharmacologically isolated inward Ca2+ current elicited by a depolarizing step. At 20 degrees C, suppression was maximal 10-25 s following the brief puff of peptide, and lasted up to 90 s. Bath application of peptide had a steady suppressing effect, showing little if any desensitization. 3. Alternative sources of inward current suppression were ruled out, indicating that application of FMRFamide or YGG-FMRFamide produces a true decrease in Ca2+ current, rather than enhancement of possible contaminating outward (K+, H+ or Cl-) currents. 4. FMRFamide and YGG-FMRFamide were equally effective in suppressing Ca2+ current (apparent dissociation constant, KD* approximately 10 microM). However, only 30-50% of the total Ca2+ current elicited by voltage steps to above +10 mV appeared to be susceptible to suppression by even saturating concentrations of peptide. This, as well as a reduced effect of the peptides on Ca2+ current which was observed at potentials below +10 mV, may perhaps result from the presence of more than one class of Ca2+ channels, only one of which is sensitive to FMRFamide. 5. FMRFamide eliminated a constant fraction of Ca2+ current at all potentials above +10 mV, and had no direct effect on activation or inactivation of the remaining current. This behaviour is consistent with reduction in the number of functional Ca2+ channels by the peptide. 6. Suppression of Ca2+ current produced a concomitant depression of Ca2+-dependent K+ current, which was shown previously to be insensitive to FMRFamide when activated by direct ionophoretic injection of Ca2+ into the cell. 7. The effect of FMRFamide on Ca2+ current was normal following interference with or activation of known second-messenger systems, those involving adenosine 3',5'-cyclic monophosphate (cyclic AMP), cyclic GMP, Ca2+, inositol trisphosphate and protein kinase C. 8. Suppression of Ca2+ current by FMRFamide appeared to be mediated by the same receptor as enhancement by the peptide of K+ current resembling IK(S) (K+ current suppressed by serotonin), an effect seen in most of the same cells. Both effects of FMRFamide were mimicked by injection of guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) into the cell, suggesting that the peptide may exert its effects by activating a guanosine 5'-triphosphate (GTP)-binding protein
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PMID:Suppression of calcium current by an endogenous neuropeptide in neurones of Aplysia californica. 244 95

The voltage- and time-dependent slow channels in the myocardial cell membrane are the major pathway by which Ca2+ ions enter the cell during excitation for initiation and regulation of the force of contraction of cardiac muscle. These slow channels appear to behave kinetically, on a population basis, as if their gates open, close, and recover more slowly than those of the fast Na+ channels. In addition, the slow channel gates operate over a less negative (more depolarized) voltage range. Tetrodotoxin does not block the slow channels, whereas the calcium antagonistic drugs, Mn2+, Co2+, and La3+ ions do. The slow channels have some special properties, including functional dependence on metabolic energy, selective blockade by acidosis, and regulation by the intracellular cyclic nucleotide levels. Because of these special properties of the slow channels, Ca2+ influx into the myocardial cell can be controlled by extrinsic factors (such as autonomic nerve stimulation or circulating hormones) and by intrinsic factors (such as cellular pH or ATP level). During transient regional ischemia, the selective blockade of the slow channels, which results in depression of the contraction and work of the afflicted cells, might protect the cells against irreversible damage by helping to conserve their ATP content. Reperfusion arrhythmias may be caused by the breakdown of this protective mechanism, in that, upon reperfusion, the Ca2+ slow channels may recover before the cells are capable of handling the greater Ca2+ influx (Fig. 20). As depicted in this figure, the Ca2+ slow channels may recover their function before the ATP level is sufficiently recovered to allow bail-out of the intracellular Ca2+. In addition, the generation of free radicals upon reperfusion may injure the Ca-ATPase and other enzymes involved in Ca2+ metabolism. The net effect of this would be to cause Ca2+ overload of the cells and SR, with subsequent delayed after-depolarizations (DADs) leading to triggered automaticity and arrhythmias. Following blockade of the fast Na+ channels in myocardial cells with TTX or by voltage-inactivating them in 25 mM (K)0, catecholamines, angiotensin-II, histamine, and methylxanthines rapidly allow the production of slowly-rising Ca2+-dependent action potentials by increasing the number of Ca2+ slow channels available for voltage activation and/or their mean open time. Concomitantly, these compounds rapidly elevate intracellular cyclic AMP levels, suggesting that cyclic AMP is somehow related to the functioning of the slow channels. Exogenous cyclic AMP produces the same effect, but much more slowly.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of calcium slow channels of cardiac muscle by cyclic nucleotides and phosphorylation. 245 7

The synthesis of carnosine (beta-Ala-His) by astroglia-rich primary cultures was much higher if the cells were cultivated in Ham's nutrient mixture F-12 than if they were grown in Dulbecco's modified Eagle's medium. Carnosine synthesis was not affected by the presence of insulin, transferrin, phorbol myristate acetate, or dexamethasone. However, dibutyryl cyclic AMP and other agents that can, directly or indirectly, activate cyclic AMP-dependent protein kinases strongly lower the rate of carnosine synthesis. The depression of carnosine synthesis was dependent on the concentration of dibutyryl cyclic AMP. The effect was maximal (approximately 80% inhibition) in cultures preincubated with 1 mM dibutyryl cyclic AMP for 4 days. The adenylate cyclase activator forskolin, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, and 8-bromo-cyclic AMP caused the same depression as dibutyryl cyclic AMP, whereas neither butyrate nor dibutyryl cyclic GMP elicited any effect.
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PMID:Regulation by dibutyryl cyclic AMP of carnosine synthesis in astroglia-rich primary cultures kept in serum-free medium. 246 17


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