Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Nitric oxide (NO) donors were recently shown to produce biphasic contractile effects in cardiac tissue, with augmentation at low NO levels and depression at high NO levels. We examined the subcellular mechanisms involved in the opposing effects of NO on cardiac contraction and investigated whether NO modulates contraction exclusively via guanylyl cyclase (GC) activation or whether some contribution occurs via cGMP/PKG-independent mechanisms, in indo 1-loaded adult cardiac myocytes. Whereas a high concentration of the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 100 micromol/L) significantly attenuated contraction amplitude by 24.4+/-4.5% (without changing the Ca2+ transient or total cAMP), a low concentration of SNAP (1 micromol/L) significantly increased contraction amplitude (38+/-10%), Ca2+ transient (26+/-10%), and cAMP levels (from 6.2 to 8.5 pmol/mg of protein). The negative contractile response of 100 micromol/L SNAP was completely abolished in the presence of the specific blocker of PKG KT 5823 (1 micromol/L); the positive contractile response of 1 micromol/L SNAP persisted, despite the presence of the selective inhibitor of GC 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 micromol/L) alone, but was completely abolished in the presence of ODQ plus the specific inhibitory cAMP analog Rp-8-CPT-cAMPS (100 micromol/L), as well as by the NO scavenger oxyhemoglobin. Parallel experiments in cell suspensions showed significant increases in adenylyl cyclase (AC) activity at low concentrations (0.1 to 1 micromol/L) of SNAP (AC, 18% to 20% above basal activity). We conclude that NO can regulate both AC and GC in cardiac myocytes. High levels of NO induce large increases in cGMP and a negative inotropic effect mediated by a PKG-dependent reduction in myofilament responsiveness to Ca2+. Low levels of NO increase cAMP, at least in part, by a novel cGMP-independent activation of AC and induce a positive contractile response.
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PMID:Activation of distinct cAMP-dependent and cGMP-dependent pathways by nitric oxide in cardiac myocytes. 1032 39

The involvement of adenosine on the development of time-dependent reversal of long-term potentiation (LTP) by low-frequency stimulation (LFS) was investigated at Schaffer collateral-CA1 synapses of rat hippocampal slices. A train of LFS (2 Hz, 10 min, 1200 pulses) had no long-term effects on synaptic transmission but produced lasting depression of previously potentiated responses. This reversal of LTP (depotentiation) was observed when the stimulus was delivered </=3 min after induction of LTP. However, application at 10 min after induction had no detectable effect on potentiation. This time-dependent reversal of LTP by LFS appeared to be mediated by extracellular adenosine, because it was mimicked by bath-applied adenosine and was specifically inhibited by the selective A(1) adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM). The effect of adenosine could be mimicked by 5-HT(1A) receptor agonist buspirone, but the LFS-induced depotentiation could not be antagonized by 5-HT(1A) receptor antagonist NAN-190. The source of extracellular adenosine in response to LFS appeared to be attributable to the efflux of cAMP. In addition, this LFS-induced depotentiation was blocked by bath application of adenylyl cyclase activator forskolin or injection of a cAMP analog Sp-adenosine cAMP (10 mM) into postsynaptic neurons. Moreover, the selective protein phosphatase 1 and 2A inhibitors okadaic acid and calyculin A prevented the LFS-induced depotentiation. These results thus suggest that increasing extracellular adenosine appears to underlie the LFS-induced depotentiation via acting on the A(1) receptor subtype to interrupt the cAMP-dependent biochemical processes leading to the LTP expression.
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PMID:A role for extracellular adenosine in time-dependent reversal of long-term potentiation by low-frequency stimulation at hippocampal CA1 synapses. 1055 82

Long-term potentiation (LTP) and long-term depression (LTD) are two main forms of activity-dependent synaptic plasticity that have been extensively studied as the putative mechanisms underlying learning and memory. Current studies have demonstrated that prior synaptic activity can influence the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. Here, we show that prior short-term synaptic disinhibition induced by type A gamma-aminobutyric acid (GABA) receptor antagonist picrotoxin exhibited a facilitation of LTP induction and an inhibition of LTD induction. This effect lasted between 10 and 30 min after washout of picrotoxin and was specifically inhibited by the L-type voltage-operated Ca2+ channel (VOCC) blocker nimodipine, but not by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphopentanoic acid (D-APV). Moreover, this picrotoxin-induced priming effect was mimicked by forskolin, an activator of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), and was blocked by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22536) and the PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS). It was also found that following picrotoxin application, CA1 neurons have a higher probability of synchronous discharge in response to a population of excitatory postsynaptic potential (EPSP) of fixed slope (EPSP/spike potentiation). However, picrotoxin treatment did not significantly affect paired-pulse facilitation (PPF). These findings suggest that a brief of GABAergic disinhibition can act as a priming stimulus for the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. The increase in Ca2+ influx through L-type VOCCs in turn triggering a cAMP/PKA signalling pathway is a possible molecular mechanism underlying this priming effect.
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PMID:Prior short-term synaptic disinhibition facilitates long-term potentiation and suppresses long-term depression at CA1 hippocampal synapses. 1058 94

The 5-HT1A receptor is implicated in depression and anxiety. This receptor couples to G(i) proteins to inhibit adenylyl cyclase (AC) activity but can stimulate AC in tissues (e.g. hippocampus) that express ACII. The role of ACII in receptor-mediated stimulation of cAMP formation was examined in HEK-293 cells transfected with the 5-HT1A receptor, which mediated inhibition of basal and G(s)-induced cAMP formation in the absence of ACII. In cells cotransfected with 5-HT1A receptor and ACII plasmids, 5-HT1A agonists induced a 1. 5-fold increase in cAMP level. Cotransfection of 5-HT1A receptor, ACII, and Galpha(i2), but not Galpha(i1), Galpha(i3), or Galpha(o), resulted in an agonist-independent 6-fold increase in the basal cAMP level, suggesting that G(i2) preferentially coupled the receptor to ACII. The 5-HT1B receptor also constitutively activated ACII. Constitutive activity of the 5-HT1A receptor was blocked by pertussis toxin and the Gbetagamma antagonist, betaCT, suggesting an important role for Gbetagamma-mediated activation of ACII. The Thr-149 --> Ala mutation in the second intracellular domain of the 5-HT1A receptor disrupted Gbetagamma-selective activation of ACII. Spontaneous 5-HT1A receptor activity was partially attenuated by 5-HT1A receptor partial agonists with anxiolytic activity (e.g. buspirone and flesinoxan) but was not altered by full agonists or antagonists. Thus, anxiolytic activity may involve inhibition of spontaneous 5-HT1A receptor activity.
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PMID:Constitutive G(i2)-dependent activation of adenylyl cyclase type II by the 5-HT1A receptor. Inhibition by anxiolytic partial agonists. 1058 18

The paper discusses therapeutical approaches to Alzheimer's disease on the basis of pathological mechanisms responsible for neurodegeneration. Amyloid plaques called also senile plaques situated extracellularly cause loss of neurons, especially cholinergic neurons, that begin in Nucleus of Meynert. However, recent evidence from postmortem brain and fibroblast studies suggests that both adenylyl cyclase and phosphatidylinositol hydrolysis signal transduction cascades are disrupted in AD. Such disruption may limit cholinergic pharmacotherapy. Other disorders, like disturbances in releasing Neuronal Growth Factor (NGF), oxidative stress, free Ca 2+, neuroimmunologic reactions are also important in AD brain changer. Only use of acetylcholine inhibitors: tacrine, donepezil and Gingko Biloba as well as nimodipine improved mental functions (MMSE screening). Neuroprotection of selegiline and NGF was observed. Behavioral symptoms often associated with dementia, like depression, anxiety, irritability, delusions, aggressiveness were treated with: olazepine, risperidone, haloperidol, clozapine, fluoxetine, paroxetine, sertraline, trazodon, dezypramine, lithium, benzodiazepines, carbamazepine and valproic acid. Drugs with strong anticholinergic effects, such as amitriptyline or imipramine should not be administered. Future studies on therapy to regulate metabolism of amyloid precursor-beta-APP are necessary to discover new efficient strategies.
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PMID:[Trials and perspectives in pharmacotherapy of Alzheimer's disease]. 1078 33

Stress results in alterations in behavior and physiology that can be either adaptive or maladaptive. To define the molecular pathways involved in the response to stress further, we generated mice deficient (KO) in the calcium-stimulated adenylyl cyclase type VIII (AC8) by homologous recombination in embryonic stem cells. AC8 KO mice demonstrate a compromise in calcium-stimulated AC activity in the hippocampus, hypothalamus, thalamus, and brainstem. Hippocampal slices derived from AC8 KO mice fail to demonstrate CA1-region long-term depression after low-frequency stimulation, and AC8 KO mice also fail to activate CRE-binding protein in the CA1 region after restraint stress. To define the behavioral consequences of AC8 deficiency, we evaluated AC8 KO mice in the elevated plus-maze and open field. Although naive AC8 KO mice exhibit indices of anxiety comparable with that of wild-type mice, AC8 KO mice do not show normal increases in behavioral markers of anxiety when subjected to repeated stress such as repetitive testing in the plus-maze or restraint preceding plus-maze testing. These results demonstrate a novel role for AC8 in the modulation of anxiety.
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PMID:Altered stress-induced anxiety in adenylyl cyclase type VIII-deficient mice. 1086 38

Endogenous adenosine in nervous tissue, a central link between energy metabolism and neuronal activity, varies according to behavioral state and (patho)physiological conditions, it may be the major sleep propensity substance. The functional consequences of activation of the four known adenosine receptors, A1, A2A, A2B and A3, are considered here. The mechanisms and electrophysiological actions, mainly those of the A1-receptor, have been extensively studied using in vitro brain-slice preparations. A1-receptor activation inhibits many neurons postsynaptically by inducing or modulating ionic currents and presynaptically by reducing transmitter release. A1-receptors are almost ubiquitous in the brain and affect various K+ (Ileak, IAHP), mixed cationic (Ih), or Ca2+ currents, through activation of Gi/o-proteins (coupled to ion channels, adenylyl cyclase or phospholipases). A2A-receptors are much more localized, their functional role in the striatum is only just emerging. A2B- and A3-receptors may be affected in pathophysiological events, their function is not yet clear. The cAMP-PKA signal cascade plays a central role in the regulation of both neural activity and energy metabolism. Under conditions of increased demand and decreased availability of energy (such as hypoxia, hypoglycemia and/or excessive neuronal activity), adenosine provides a powerful protective feedback mechanism. Interaction with adenosine metabolism is a promising target for therapeutic intervention in neurological and psychiatric diseases such as epilepsy, sleep, movement (parkinsonism or Huntington's disease) or psychiatric disorders (Alzheimer's disease, depression, schizophrenia or addiction).
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PMID:Functions of neuronal adenosine receptors. 1111 31

An animal model most sensitive for measuring anticipatory anxiety is fear conditioning, which is expressed by an enduring increase in synaptic strength in the amygdala. A converse view predicts that agents that induce long-term depression (LTD) of synaptic efficacy in the amygdala may be useful in the amelioration of stress disorders. In the present study, we show that activation of group II metabotropic glutamate receptor (mGluR II) by (2S,3S, 4S)-2-(carboxycyclopropyl) glycine (l-ccg) induces an LTD in the basolateral amygdala neurons. The effect was concentration-dependent with a maximal inhibition of approximately 30%. The induction of l-CCG LTD required concurrent synaptic activity, required presynaptic but not postsynaptic Ca(2+) increases, and was independent of NMDA receptors. l-CCG LTD was associated with an increase in the ratio of paired-pulse facilitation and was not occluded by low-frequency stimulation-induced LTD, suggesting that these two forms of LTD did not share a common underlying mechanism. After eliciting LTD with l-CCG, application of isoproterenol increased the synaptic responses back to its original baseline, demonstrating that chemically depressed synapses could be potentiated by another chemical. A selective PKA inhibitor, KT 5720, by its own caused a depression of synaptic transmission and blocked l-CCG LTD, presumably by mimicking and thereby occluding any further depression. Together, these results suggest that l-CCG LTD is induced by presynaptically mGluR II-mediated inhibition of Ca(2+)-sensitive adenylyl cyclase, resulting in a decrease in cAMP formation and PKA activation, which leads to a long-lasting decrease in transmitter release.
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PMID:Activation of group II metabotropic glutamate receptors induces long-term depression of synaptic transmission in the rat amygdala. 1112 77

N-Acetylaspartylglutamate (NAAG) is an agonist at the type 3 metabotropic glutamate receptor (mGluR3), which is coupled to a Gi/o protein. When activated, the mGluR3 receptor inhibits adenylyl cyclase and reduces the cAMP-mediated second-messenger cascade. Long-term potentiation (LTP) in the medial perforant path (MPP) of the hippocampal dentate gyrus requires increases in cAMP. The presence of mGluR3 receptors and NAAG in neurons of the dentate gyrus suggests that this peptide transmitter may inhibit LTP in the dentate gyrus. High-frequency stimulation (100 Hz; 2 s) of the MPP resulted in LTP of extracellularly recorded excitatory postsynaptic potentials at the MPP-granule cell synapse of rat hippocampal slices. Perfusion of the slice with NAAG (50 and 200 microM) blocked LTP. Neither 50 nor 200 microM NAAG produced N-methyl-D-aspartate receptor currents in the granule cells of the acute hippocampal slice. The group II mGluR antagonist ethyl glutamate (100 microM) and a structural analogue of NAAG, beta-NAAG (100 microM), prevented the blockade of LTP by NAAG. Paired-pulse depression of the excitatory postsynaptic potential at 20- and 80-ms interpulse intervals (IPI) was not affected by NAAG or beta-NAAG. beta-NAAG did not affect inositol trisphosphate production stimulated by the agonist glutamate in cells expressing the group I mGluR1alpha or mGluR5. beta-NAAG blocked the decrease in forskolin-stimulated cAMP by the group II mGluR agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) but not the group III mGluR agonist L(+)-2-amino-4-phosphonobutyric acid in cerebellar granule cells. In cells transfected with mGluR3, but not mGluR2, beta-NAAG blocked forskolin-stimulated cAMP responses to glutamate, NAAG, the nonspecific group I, II agonist trans-ACPD, and the group II agonist DCG-IV. We conclude that beta-NAAG is a selective mGluR antagonist capable of differentiating between mGluR2 and mGluR3 subtypes and that the mGluR3 receptor functions to regulate activity-dependent synaptic potentiation in the hippocampus.
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PMID:beta-NAAG rescues LTP from blockade by NAAG in rat dentate gyrus via the type 3 metabotropic glutamate receptor. 1124 80

A new anticonvulsant drug lamotrigine (LTG) has recently been reported to be effective in treating patients with bipolar affective disorder, depression and schizoaffective disorder, suggesting that it is a mood stabilizer. However, the mechanism of action underlying its efficacy in mood disorders is not understood. This study examined the in vivo effect of LTG on 5-HT(1A) receptor-mediated adenylyl cyclase (AC) response in regions of rat brain, as this pathway has been implicated in the therapeutic action of various classes of mood stabilizers. The density of 5-HT(1A) receptors was measured by radioligand binding assay using [(3)H]8-OH-DPAT (0.05-0.8nM) in frontal cortex and hippocampus of rats treated orally with LTG (5mg/kg) for 7 days. AC activity was assayed using [(3)H]ATP. The oral administration of LTG significantly decreased the density of cortical (50%, P<0.001) but not hippocampal 5-HT(1A) receptors, without significant change in the affinity of [(3)H]8-OH-DPAT to 5-HT(1A) receptor in these regions. There was no significant alteration in basal or forskolin-stimulated AC activity in either of regions. However, a significant decrease (P<0.01) in the inhibition of forskolin-stimulated AC activity by 8-OH-DPAT was observed only in cortical membranes of LTG treated rats when compared to control. These results suggest that one mode of action of LTG may be by the downregulation of cortical 5-HT(1A) receptor-mediated AC response.
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PMID:Lamotrigine induced selective changes in 5-HT(1A) receptor mediated response in rat brain. 1179 61


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