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

Hormonal modulation of neurotransmission emerged as a concept from the recognition that adrenocortical steroids exert profound effects at the level of receptors, G-proteins and effector units. G-proteins, a family of guanine nucleotide binding regulatory components that couple neurotransmitter receptors to various types of intracellular effector systems, appear to be a key target of glucocorticoid (GC) action in the CNS. It is thought that Gs/Gi mediates stimulation/inhibition of adenylate cyclase (AC system), which forms cyclic AMP as second messenger, while receptors stimulating phospholipase C do so through Go to produce two second messengers, inositol 1,4,5-triphosphate and diacylglycerol (PI system). Recent evidence suggests that GC increase Gs alpha-and decrease Gi alpha-protein subunit expression without affecting Go alpha. Activation of central pre- and postsynaptic 5-HT1A receptors which are linked to the Gi-AC complex, induces hypothermia and ACTH/cortisol release in rodents and humans. Compared with controls, patients with a major depressive disorder exhibit increased basal cortisol secretion associated with decreased hypothermic and ACTH/cortisol responses. The attenuated neuroendocrine and thermoregulatory response to 5-HT1A receptor activation may reflect a GC-dependent feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) system and subsensitivity of the presynaptic 5-HT1A-Gi-AC complex function. Differential regulation of 5-HT1A and 5-HT2 function leading to a relative 5-HT2-Go-PI complex supersensitivity may maintain HPA hyperactivity during the course of depression. These findings corroborate recent reports that GC, via GC-GC receptor (GR) complex activated promotion of gene transcription, modify the expression 5-HT1A-coupled Gi (but not 5-HT2-coupled Go) resulting in altered sensitivity of 5-HT1A-mediated signal transduction and further support the hypothesis of a differential regulation of 5-HT1A and 5-HT2 receptor function and a GC-GR/5-HT1A-G-protein--effector system-related abnormality in depression.
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PMID:The 5-HT receptor--G-protein--effector system complex in depression. I. Effect of glucocorticoids. 164 69

1. After blocking K+ currents with 10 mM-tetraethylammonium (TEA) or TEA plus 250 microM-3,4-diaminopyridine (3,4-DAP). motor nerve terminal Ca2+ currents were recorded using focal extracellular electrodes. Two transmitters released from the terminal. ATP and acetylcholine (ACh), were then applied, and the effects on the nerve terminal Ca2+ current were measured. 2. ATP (50 microM) reduced the Ca2+ current by 34%, but this action is prevented when hydrolysis to adenosine is blocked by alpha,beta-methyladenosine 5'-diphosphate (200 microM). Thus, inhibition by ATP presumably occurs subsequent to ATP hydrolysis to adenosine. 3. Adenosine (50 microM) inhibited the terminal Ca2+ current by 29%. This was mimicked by the adenosine analogue L-phenylisopropyl adenosine (L-PIA) and blocked by theophylline (100 microM), which antagonizes adenosine receptors at micromolar concentrations. 4. ACh (100 microM) or the anticholinesterase methane sulphonyl fluoride (MSF; 1 mM) also depressed the terminal Ca2+ current. This response was mimicked by muscarine (100 microM) and antagonized by atropine (100 microM) or pirenzipine (4 microM), which is generally specific for M1 receptors. 5. Addition of Ba2+, which blocks adenosine-mediated K+ currents, had no effect on the inhibitory effects of either adenosine or ACh; similarly, neither adenosine nor ACh in the bath affected K+ current records obtained after blocking all inward currents with 10 mM-Co2+ and focal application of tetrodotoxin. 6. Incubation of the muscle for 4 h in pertussis toxin (10(-5) g ml-1) eliminated both adenosine- and ACh-induced inhibition of the terminal Ca2+ current. This result indicates the possible involvement of a G protein in the transduction of the feedback pathway. 7. Neither cyclic AMP analogues, the adenylate cyclase activator forskolin (10 microM), the phorbol ester phorbol 12-myristate 13-acetate (PMA; 3 microM) nor the diacylglycerol analogue 1,2-oleoylacetylglycerol (OAG; 3 microM) had any effect on adenosine- or ACh-induced depression of the terminal Ca2+ current. Therefore, pathways involving these particular second messengers are most probably not involved. 8. The effects of adenosine and ACh are non-additive. 9. These results indicate that ATP and ACh, which are released during exocytosis, may inhibit their own release through attenuation of the terminal Ca2+ current via autoreceptors coupled to a G protein.
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PMID:Autoreceptor-mediated purinergic and cholinergic inhibition of motor nerve terminal calcium currents in the rat. 165 22

CK-2289 is an inhibitor of type III cyclic 3'5'-adenosine monophosphate phosphodiesterase with potential utility in the treatment of congestive heart failure. We compared CK-2289 to milrinone and enoximone in several pharmacological models. Intravenous administration of CK-2289 to pentobarbital-anesthetized dogs (0.03 to 1 mg/kg) produced dose-related increases in myocardial dP/dTmax and decreased mean arterial blood pressure, similar to milrinone and enoximone. However, CK-2289 was 3-9 times more potent than either agent as a positive inotrope. Intraperitoneal and oral administration of CK-2289 and milrinone to mice produced central nervous system depression. Administered intravenously. CK-2289 and milrinone (1 mg/kg) inhibited, whereas enoximone (1 mg/kg) enhanced, guinea-pig gastric acid secretion. CK-2289 (0.01 to 0.3 mg/kg) and milrinone (0.03 to 1 mg/kg), given intravenously, did not affect neurotransmission to the rabbit sciatic nerve-gastrocnemius muscle preparation. Neither CK-2289 nor milrinone (100 microM) inhibited sympathetic neurotransmission, alpha 1-, muscarinic and thromboxane receptors. Both compounds relaxed canine arteries and veins. CK-2289 was devoid of effects on non-vascular smooth muscles of guinea-pig vas deferens and uteri and rabbit bronchi. CK-2289 (1 to 100 microM), milrinone and enoximone inhibited human platelet aggregation produced by adenosine diphosphate and sodium arachidonate. These data suggest that CK-2289 should be devoid of adverse renal, neural, smooth or skeletal muscle or gastrointestinal side effects associated with milrinone and enoximone therapy.
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PMID:Pharmacological comparison of CK-2289, an inodilator agent, with milrinone and enoximone. 165 60

The membrane permeable cyclic AMP analogue dibutyryl cAMP was found to have a biphasic effect on the amplitude of population spikes recorded in area CA1 of rat hippocampal slices in response to 0.05 Hz stimulation of the Schaffer collateral/commissural path. While dbcAMP was present the population spike was depressed and after washout of dbcAMP the population spike showed potentiation lasting at least 2 h. The population excitatory postsynaptic potential (EPSP) was unaffected. Addition of picrotoxin throughout the experiment caused no change in the depression but reduced the potentiation caused by dbcAMP. We conclude that cAMP may play a role in long-term potentiation (LTP).
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PMID:Cyclic AMP induces long-term increase in synaptic efficacy in CA1 region of rat hippocampus. 166 Sep 74

1. Acetylcholine (ACh), 7.5 x 10(-5) M, and carbachol, 5 x 10(-6) M (CCh) depressed the frequency of miniature endplate potentials (m.e.p.ps) in the frog (Rana temporaria) sartorius neuromuscular junction with active acetylcholinesterase to about 50-55% of the controls. 2. A similar depression was produced by the nicotinic agonists, nicotine, suberyldicholine and tetramethylammonium. 3. The muscarinic agonists, oxotremorine, methylfurmethide and methacholine were without effect on m.e.p.p. frequency. The muscarinic antagonist, atropine and the nicotinic antagonist, (+)-tubocurarine, had no effect on the depression of m.e.p.p. frequency evoked by CCh. 4. The ganglionic blockers, benzhexonium and IEM-1119, were also without effect on the CCh-evoked depression of m.e.p.p. frequency. 5. Pretreatment of muscles with anticholinesterases did not prevent the CCh-induced drop in m.e.p.p. frequency. 6. The effect of CCh was proportionally the same as in the controls in preparations where the m.e.p.p. frequency was changed by elevation of K+ and in the presence of theophylline, noradrenaline, dibutyryl adenosine 3':5'-cyclic monophosphate (db cyclic AMP) and db cyclic GMP. 7. An inhibitor of Na+,K(+)-ATPase, ouabain, 5 x 10(-5) mol l-1, prevented or reversed the depression of m.e.p.p. frequency by CCh. However, the depression was present in a nominally K(+)-free medium. Insulin and adrenaline, which are considered to be Na+,K(+)-ATPase activators, were without effect on depression of m.e.p.p. frequency. 8. The depression of m.e.p.p. frequency by 5 x 10(-6) M CCh was the same at temperatures between 5 and 30 degrees C with a Q10 near to 1.0. When threshold amounts of CCh were used (6 x 10-7 and 3 x 10-7 M), the depression was less at higher temperatures.9. The receptive structures responsible for the CCh (or ACh)-evoked depression of m.e.p.p. frequency differ pharmacologically from muscarinic, nicotinic ganglionic and neuromuscular junction ACh-receptors as well as from the synaptic cholinesterase, in contrast to previous reports (Duncan & Publicover, 1979).The low temperature-dependence points to the possibility that physical rather than biochemical processes are limiting in this presynaptic effect of cholinomimetics.
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PMID:Depression of miniature endplate potential frequency by acetylcholine and its analogues in frog. 166 83

1. The whole-cell patch-clamp technique was used to record membrane currents from neurones which were acutely dissociated from the intra-atrial parasympathetic ganglia of Rana pipiens. The effects of muscarine and adrenaline were observed at a holding potential of -30 mV. Extracellular potassium concentration ([K+]o) was 2, 6 or 20 mM. 2. Muscarine (10 microM) produced inward current in thirteen cells, outward current in eighteen cells and seven cells were unaffected. Inward currents were observed in six out of ten neurones in which the intracellular solution contained adenosine triphosphate (ATP; 100 microM) and outward currents were seen in eleven out of fourteen neurones which contained adenosine 3',5'-cyclic monophosphate (cyclic AMP; 100 microM). 3. In five out of nine cells tested, the inward current produced by muscarine was attributable to a 30% depression of a voltage-dependent current which resembled the M-current (IM). Muscarine-induced inward current in the other four cells involved a steady-state conductance increase that reached a null potential at -10 mV. Modest IM suppression also contributed to the response in three of these four cells. 4. Adrenaline (10 or 100 microM) produced inward currents in twelve cells, outward current in ten cells and three cells were unaffected. Outward currents were only seen in cells which contained ATP or cyclic AMP (ten out of sixteen cells) whereas inward currents were seen in eight out of nine cells which did not contain adenosine nucleotides. These inward currents were always attributable to IM suppression. 5. The outward currents induced by muscarine and adrenaline resulted from an increase in a potassium conductance (GK) that exhibited inward rectification.
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PMID:The effects of muscarine and adrenaline on patch-clamped frog cardiac parasympathetic neurones. 166 40

1. The longitudinal muscle from the uterus of oestrogen-treated rats was quiescent in Mg-free Krebs solution. Electrical stimulation generated phasic contraction, which was depressed to 35% and 18% by 50 mu and 150 mu porcine relaxin, respectively. 2. The phasic contractions were more strongly depressed to 26% by 50 mu relaxin in solution containing 0.6 mM Mg, and the depression lasted for more than 4 h after the removal of relaxin. During the persisting depression, raising the external Ca to 7.5 mM did not restore the contraction, but the contraction was restored by removal of Mg. 3. The depression of the phasic contraction by relaxin, examined in Mg-free solution, was enhanced and reduced by pretreatment of the tissue with 0.6 mM Mg and 0.6 mM Mn, respectively, for about 15 min. In contrast, the depression of contraction by isoprenaline or forskolin was enhanced by pretreatment with either Mg or Mn. 4. The cellular content of cyclic AMP was measured in Krebs solution containing 0.6 mM Mg. The values were 1.24 (pmol mg-1 protein) in control solution, and 2.31 and 1.56 when the tissues were treated with 150 mu relaxin and 10(-9) M isoprenaline, respectively. 5. The cyclic AMP production in response to 10(-7) M forskolin measured in Mg-free solution was enhanced when the tissue was pretreated with either 0.6 mM Mg or Mn for 15 min. The cyclic AMP production in response to 100 mu relaxin was increased when the tissue was pretreated with 0.6 mM Mg, and was unchanged by pretreatment with Mn. The cyclic AMP production in response to 10(-9) M isoprenaline was unchanged by pretreatment with the divalent cations. 6. The membrane potential of the muscle was -60.8 mV in Krebs solution containing 0.3 mM Mg, and electrical stimulation induced an action potential which consisted of spike and plateau components. Application of 150 mu relaxin reduced the duration of the plateau; the contractions were progressively depressed. The resting membrane potential and membrane resistance were unchanged by application of 150 mu relaxin. The membrane was hyperpolarized by 2.8 mV, accompanied by a decrease in membrane resistance, when 10(-9) M isoprenaline was applied. 7. Although there were several differences between the effects of relaxin and isoprenaline, it is probable that some process, which is cyclic AMP-dependent, accelerated by Mg and depressed by Mn, is involved in the depressant action of relaxin on contraction.
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PMID:Effects of porcine relaxin on contraction, membrane response and cyclic AMP content in rat myometrium in comparison with the effects of isoprenaline and forskolin. 168 69

Prostacyclin and beraprost sodium (beraprost), a stable analogue of prostacyclin, increased cyclic AMP (cAMP) levels of cultured human umbilical vein endothelial cells (HUVEC) in a concentration-dependent manner. The elevation of cAMP by beraprost was sustained longer than that by prostacyclin. The expression of thrombomodulin (TM) on membrane surface of HUVEC was enhanced by beraprost and prostacyclin, and the persistence of the increase in TM expression by beraprost was greater than prostacyclin. Dibutyryl cAMP (db-cAMP) mimicked the effects of beraprost and 3-isobutyl-1-methylxanthine enhanced the effects. Beraprost, prostacyclin and db-cAMP also effectively blocked the interleukin-1- and tumor necrosis factor-induced depression of TM expression substantially. These results suggest that TM expression is positively regulated by cAMP in HUVEC, and that beraprost may be potentially effective for reducing thrombotic events through the mechanism which initiates the stimulation of cAMP/TM system in vascular endothelial cells.
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PMID:Enhancement by beraprost sodium, a stable analogue of prostacyclin, in thrombomodulin expression on membrane surface of cultured vascular endothelial cells via increase in cyclic AMP level. 170 20

The effect of dipyridamole (DYP) on postischemic myocardial function and metabolism was studied using the isolated rabbit heart model. Twenty-one isolated rabbit heart preparations were divided into two groups: KH (control N = 10) were reperfused after 24 min normothermic hyperkalemic arrest with modified Krebs-Henseleit buffer (KH) while DYP (N = 11) were reperfused with KH and 5 X 10(-6) M DYP. Hearts were analyzed for myocardial function (DP, developed pressure, +dp/dt, -dp/dt) and metabolic function (ATP, CrP, ADP, AMP, purines, and lactate levels). Data analysis revealed significant reperfusion depression in DYP myocardial function compared with KH (P less than 0.05): DP (42 +/- 6 vs 89 +/- 7 mm Hg), +dp/dt (390 +/- 21.6 vs 1227 +/- 48.4), and -dp/dt (280 +/- 20.1 vs 677 +/- 19.8). Comparison of DYP to KH metabolic parameters was also significantly different (P less than 0.05): ATP (5.8 +/- 0.7 vs 9.5 +/- 1.4), ADP (2.1 +/- 0.2 vs 3.2 +/- 0.6), CrP (9.6 +/- 0.3 vs 17.2 +/- 1.3). Tissue purines (adenosine and inosine) were significantly elevated (P less than 0.01) in the DYP group, while coronary sinus purines and lactate loss were similar. Thus, the data suggest that DYP, present during postischemic reperfusion, depresses myocardial function by inhibiting adenosine phosphorylation, thereby decreasing the generation of high-energy phosphates without increased substrate loss or ischemia.
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PMID:Metabolic and functional cardiac impairment after reperfusion with persantine. 186 75

The present study aimed to study the relation between the release of arachidonic acid (AA) and the energy state in cerebral cortices of rats during single episodes of cortical spreading depression (CSD). The changes in concentrations of AA, labile phosphate compounds [ATP, ADP, AMP, and phosphocreatine (PCr)], and glycolytic metabolites (lactate, pyruvate, glucose, and glycogen) were studied during and following the large change of the local direct current (DC) potential. Free AA increased markedly during the DC shift, continued to increase during the subsequent 3 min, and returned to control levels at 4-5 min after CSD. PCr decreased by 38% in the first minutes following the DC shift, while ADP increased by 38%. Both returned to normal within a few minutes. ATP, AMP, and energy charge remained constant throughout the experimental period. Glucose decreased by 47% and glycogen by 34% for a few minutes following CSD, while lactate increased by 105% at 2-3 min and by 77% at 4-5 min after CSD. The metabolites returned to control levels at 10 min after CSD. Considering the constant energy charge at all time points during CSD, it is suggested that the AA rise reflects augmented phospholipase activity due to either increased intracellular [Ca2+] or receptor stimulation or both. The possibility that N-methyl-D-aspartate receptors play a role in the release of AA, and that free AA in turn could be part of the mechanism of CSD, is discussed.
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PMID:Cortical spreading depression is associated with arachidonic acid accumulation and preservation of energy charge. 210 27


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