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)

Confocal laser scanning microscopy was used to study changes in intracellular free calcium concentration ([Ca2+]i) at the level of the soma of cultured hippocampal neurones following pressure application of glutamate or N-methyl-D-aspartate (NMDA). [Ca2+]i was imaged in the presence of tetrodotoxin after loading cells with the fluorescent dye indicator fluo-3/AM. Responses to glutamate were potently antagonized by 6-cyano-7 nitroquinoxaline-2,3-dione (CNQX: 20 microM). They were also strongly and reversibly depressed by 3-((+/-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP; 20 microM), leaving a small CNQX-sensitive component. Responses to NMDA were also blocked by CNQX. In the presence of saturating concentrations of glycine (100 microM), the depression of glutamate or NMDA responses by CNQX was greatly reduced. Exogenously applied glycine also potentiated the NMDA response. These data indicate that the glycine binding site of the NMDA receptor channel is not saturated in cultured hippocampal neurones and thus is susceptible to the action of agonists or antagonists.
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PMID:Changes in intracellular calcium induced by NMDA in cultured rat hippocampal neurons require exogenous glycine. 876 83

Beginning at therapeutic concentrations (1-1.5mM), the anti-manic-depressive drug, lithium, stimulated the release of the major excitatory central neurotransmitter, glutamate, in monkey cerebral cortex slices in a time- and concentration-dependent manner, and this was associated with increased inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] accumulation. (+/-)-3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphoric acid (CPP), dizocilpine (MK-801), ketamine, and Mg(2+)-antagonists to the N-methyl D-aspartate (NMDA) receptor/channel complex selectivity inhibited lithium-stimulated Ins(1,4,5)P3 accumulation. Antagonists to cholinergic-muscarinic, alpha 1-adrenergic, 5-HT2-serotoninergic and H1-histaminergic receptors had no effect. Antagonists to non-NMDA glutamate receptors had no effect on lithium-stimulated Ins(1,4,5)P3 accumulation. Possible reasons for this are discussed. Similar results were obtained in mouse cerebral cortex slices. Carbetapentane, which inhibits glutamate release, inhibited lithium-induced Ins(1,4,5)P3 accumulation in this model. It is concluded that the primary effect of lithium in the cerebral cortex slice model is stimulation of glutamate release, which, via activation of the NMDA receptor, leads to Ca2+ entry. Ca2+ entry, in turn, activates phospholipase C. These effects may have relevance to the therapeutic action of lithium in the treatment of manic-depression, as well as its toxic effects, especially at lithium blood levels above 1.5mM. A general conclusion which can be drawn from these studies and earlier studies in our laboratory is that lithium potentiates the action of phospholipase C, whether this enzyme is activated by lithium-induced presynaptic release of neurotransmitter, such as glutamate, or by the addition of an exogenous neurotransmitter, such as acetylcholine. However, this does not appear to be due to a direct activation of phospholipase C.
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PMID:A novel action of lithium: stimulation of glutamate release and inositol 1,4,5 trisphosphate accumulation via activation of the N-methyl D-aspartate receptor in monkey and mouse cerebral cortex slices. 886 49

L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC) reverses plasma membrane glutamate transporters and elevates extracellular glutamate levels in vivo. We investigated the possibility that L-trans-PDC-stimulated glutamate levels are mediated partially by increases in transsynaptic activity. Therefore, the degree to which L-trans-PDC-evoked glutamate levels depend on calcium, sodium-channel activation, and glutamate-receptor activation was investigated by infusing via reverse microdialysis (a) 0.1 mM calcium, (b) 1 microM tetrodotoxin, a selective blocker of voltage-dependent sodium channels, (c) R(-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a selective NMDA-receptor antagonist, or (d) LY293558, a selective alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate antagonist. In separate experimental groups, L-trans-PDC-evoked glutamate levels were reduced significantly by 55% in the presence of 0.1 mM calcium and by 46% in the presence of tetrodotoxin. Additionally, CPP and LY293558 significantly attenuated L-trans-PDC-evoked glutamate levels without altering basal glutamate levels. These data suggest that glutamate transporter reversal by L-trans-PDC initially elevates extracellular glutamate levels enough to stimulate postsynaptic glutamate receptors within the striatum. It is proposed that glutamate-receptor stimulation activates a positive feedback loop within the basal ganglia, leading to further glutamate release from corticostriatal and thalamostriatal afferents. Therefore, either extracellular striatal calcium reduction or tetrodotoxin perfusion leads to decreased action potential-dependent glutamate release from these terminals. In addition, blocking glutamate receptors directly reduces medium spiny neuronal firing and indirectly attenuates corticostriatal and thalamostriatal activity, resulting in an overall depression of L-trans-PDC-stimulated glutamate levels.
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PMID:L-trans-pyrrolidine-2,4-dicarboxylic acid-evoked striatal glutamate levels are attenuated by calcium reduction, tetrodotoxin, and glutamate receptor blockade. 908 26

The influence of synaptic activity on the depression of N-methyl-D-aspartate (NMDA) receptor mediated synaptic responses by the noncompetitive blocker dizocilpine and the competitive antagonist CPP (3-((R)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) was examined in the rat hippocampal slice preparation. In slices superfused by a Mg(2+)-free medium, both drugs, dizocilpine (2 to 100 microM) and CPP (0.2 to 10 microM), applied by perfusion, depressed the NMDA receptor mediated secondary population spikes (PSs) in the CA1 pyramidal cell layer. Repetitive stimulation (0.2 Hz, 5 min) greatly enhanced the depression produced by dizocilpine but was without any effect on the depression produced by CPP. In slices superfused with a normal medium, dizocilpine applied locally by pressure ejection (100 microM, 380 pL. 1 s) coupled with high-frequency stimulation (100 Hz, 1 s) prevented the appearance of multiple PSs in the subsequent 90-min period of perfusion with a Mg(2+)-free medium but was ineffective when applied without concomitant stimulation. These results indicate that the synaptic NMDA receptor mediated responses, similar to responses evoked by exogenous NMDA agonists, are depressed by dizocilpine in a use-dependent manner.
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PMID:Use-dependent depression of synaptic NMDA receptor mediated responses by dizocilpine (MK-801). 911 38

N-Methyl-D-aspartate (NMDA) receptor activation initiates both homosynaptic long-term depression (LTD) and long-term potentiation (LTP) in the CA1 region of the hippocampus. The mechanism by which two opposing forms of synaptic plasticity can be initiated through the activation of a single receptor is not known. We examined the effects of two competitive antagonists on the induction of LTP and LTD, D-2-amino-5-phosphonovaleric acid (D-AP5), a broad spectrum inhibitor of the NMDA receptor, and 3-((RS)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), an antagonist that binds with high affinity to conventional NMDA receptors subtypes, but not to atypical subtypes that are relatively independent of voltage-dependent Mg2+-blockade. As has previously been reported, LTP, LTD, and depotentiation were all blocked by applications of D-AP5. In contrast, only LTP, but not LTD or depotentiation, was blocked by CPP. These observations suggest that decreases and increases of synaptic strength are mediated by the activation of distinct NMDA receptor subpopulations.
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PMID:Long-term potentiation and long-term depression are induced through pharmacologically distinct NMDA receptors. 915 1

Spreading depression was evoked in vitro in retinas of 3-6 day old chickens by the nicotinic cholinergic agonists nicotine and cytisine. The response was reproducible and inhibited by the nicotinic cholinergic receptor antagonist mecamylamine and by the NMDA receptor antagonist -3-(2 carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP). The response to nicotinic agonists was not inhibited by alpha-bungarotoxin. The data show that spreading depression can be evoked in the chick retina by alpha-bungarotoxin insensitive nicotinic acetylcholine receptor subtypes and that the response is dependent upon NMDA receptor activation. This nicotine evoked spreading depression was inhibited by cadmium chloride indicating the involvement of voltage sensitive calcium channels. It is therefore argued that nicotine evokes spreading depression indirectly, as a result of calcium sensitive glutamate release. The glutamate released thus exerting its effects via NMDA receptors.
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PMID:The triggering of spreading depression in the chick retina by nicotinic receptor agonists. 943 Apr 15

1. Using an in vitro slice preparation of the rat dorsal lateral geniculate nucleus (dLGN), the properties of retinogeniculate and corticothalamic inputs to thalamocortical (TC) neurones were examined in the absence of GABAergic inhibition. 2. The retinogeniculate EPSP evoked at low frequency (>= 0.1 Hz) consisted of one or two fast-rising (0.8 +/- 0.1 ms), large-amplitude (10.3 +/- 1.6 mV) unitary events, while the corticothalamic EPSP had a graded relationship with stimulus intensity, owing to its slower-rising (2.9 +/- 0.4 ms), smaller-amplitude (1.3 +/- 0.3 mV) estimated unitary components. 3. The retinogeniculate EPSP exhibited a paired-pulse depression of 60.3 +/- 5.6 % at 10 Hz, while the corticothalamic EPSP exhibited a paired-pulse facilitation of > 150 %. This frequency-dependent depression of the retinogeniculate EPSP was maximal after the second stimulus, while the frequency-dependent facilitation of the corticothalamic EPSP was maximal after the fourth or fifth stimulus, at interstimulus frequencies of 1-10 Hz. 4. There was a short-term enhancement of the >= 0.1 Hz corticothalamic EPSP (64.6 +/- 9.2 %), but not the retinogeniculate EPSP, following trains of stimuli at 50 Hz. 5. The >= 0.1 Hz corticothalamic EPSP was markedly depressed by the non-NMDA antagonist 1-(4-amino-phenyl)-4-methyl-7,8-methylene-dioxy-5H-2, 3-benzodiazepine (GYKI 52466), but only modestly by the NMDA antagonist 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ((RS)-CPP), and completely blocked by the co-application of GYKI 52466, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), (RS)-CPP and (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (MK-801). Likewise, the corticothalamic responses to trains of stimuli (1-500 Hz) were greatly reduced by this combination of ionotropic glutamate receptor antagonists. 6. In the presence of GYKI 52466, CNQX, (RS)-CPP and MK-801, residual corticothalamic responses and slow EPSPs, with a time to peak of 2-10 s, could be generated following trains of five to fifty stimuli. Neither of these responses were occluded by 1S,3R-1-aminocyclopentane-1, 3-dicarboxylic acid (1S,3R-ACPD), suggesting they are not mediated via group I and II metabotropic glutamate receptors.
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PMID:Characterization of sensory and corticothalamic excitatory inputs to rat thalamocortical neurones in vitro. 966 Aug 97

In young rats, low frequency (1-2 Hz) stimulation of the Schaffer collaterals for 15 min induces in the CA1 area of the hippocampus a homosynaptic and N-methyl-D-aspartate receptor-dependent form of long-term depression (LTD) of synaptic efficacy. In the adults, while a similar stimulation paradigm is able to depress previously potentiated synapses, it leads to conflicting results when applied to naive synapses. In the present experiments, different stimulation paradigms have been used to induce LTD in the CA1 area of the adult rat hippocampus in vitro. Thus, stimulation of the afferent pathway at frequencies higher than those used to produce LTD in young animals (5-10 Hz, for 15 min) reliably induced a homosynaptic form of LTD. This form of LTD was associated with a significant increase in paired-pulse facilitation ratio and was insensitive to ionotropic (CNQX, 10 microM and CPP, 20 microM) and metabotropic (S-MCPG, 1 mM) glutamate receptors antagonists, suggesting a presynaptic mechanism for both LTD induction and expression. In conclusion, our experiments clearly show that LTD is not a purely developmental phenomenon but is present also in mature rats, which possess the whole machinery for LTD induction and this will greatly enhance the flexibility and the storing capacity of neuronal circuits.
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PMID:A novel form of long-term depression in the CA1 area of the adult rat hippocampus independent of glutamate receptors activation. 975 65

Hypoxia-induced spreading depression-like depolarization (hypoxic SD, or anoxic depolarization) is accompanied by the near-loss of membrane potential, severe reduction of membrane resistance, and influx of Na+, Ca2+, Cl- and water into neurons. The biophysical nature of these membrane changes is incompletely understood. In the present study we applied a pharmacological mixture (10 microM DNQX, 10 microM CPP, 1 microM TTX, and 2 mM Ni2+) to rat hippocampal tissue slices to inhibit major Na+ and Ca2+ inward currents. This inhibitory cocktail slightly depolarized CA1 pyramidal neurons and completely blocked all evoked potentials. In its presence severe hypoxia of up to 20 min duration failed to induce hypoxic SD and the accompanying intrinsic optical signal. Instead, only moderate, very slow negative shifts of the extracellular DC potential were observed. Following 10 min hypoxia and 1 hour wash-out of the inhibitors antidromic and orthodromic responses were still blocked but hypoxic SD with markedly delayed onset could be induced in most slices. In current-clamped CA1 pyramidal cells hypoxia induced a rapid, near-complete depolarization and decreased the input resistance by 89%. In the presence of the cocktail, however, hypoxia caused a gradual, partial depolarization, to about -40 mV; the membrane resistance decreased by only 37%. We conclude that simultaneous blockade of the known major Na+ and Ca2+ channels consistently prevents hypoxic SD. The hypothesis that SD initiation is the consequence of general loss of selective permeability or general membrane breakdown becomes unlikely. Instead, influx of Na+ and Ca2+ might play a crucial role in the generation of the rapid SD-like depolarization.
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PMID:Inhibition of major cationic inward currents prevents spreading depression-like hypoxic depolarization in rat hippocampal tissue slices. 981 18

Winter depressions in seasonal affective disorder (SAD) are associated with central serotonergic (5-HT) dysfunction. SAD patients demonstrate rather specific, state-dependent, abnormal increases in 'activation-euphoria' ratings following intravenous infusion of the 5-HT receptor agonist meta-chlorophenylpiperazine (m-CPP). Several studies are also consistent with abnormal serotonergic regulation of the hypothalamic-pituitary-adrenal (HPA) axis in SAD. Here, we investigated the effects of the 5-HT1A receptor partial agonist ipsapirone, which produces behavioral effects and HPA-axis activation, to further characterize the 5-HT receptor subtype-specificity of these disturbances in SAD. Eighteen SAD patients and 18 control subjects completed two drug challenges (ipsapirone 0.3 mg/kg and placebo) separated by 3-5 days in randomized order. We measured behavioral responses with the NIMH self-rating scale, and plasma ACTH, cortisol, and prolactin concentrations. Compared with placebo, ipsapirone was associated with significant increases in self-rated 'functional deficit' and 'altered self-reality', and in each of the hormones. There were no differences between groups on any measures. The level of depression in SAD patients was inversely correlated with their ipsapirone-induced cortisol responses. There were significant drug x order effects on baseline 'anxiety' scores, ACTH and cortisol concentrations, such that subjects were significantly more stressed (higher 'anxiety', ACTH and cortisol) prior to their first challenge compared with their second. In conclusion, post-synaptic 5-HT1A receptors appear to function normally in SAD. The previously observed m-CPP-induced behavioral abnormality may be mediated by either 5-HT2C or 5-HT7 receptors.
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PMID:Serotonin hypothesis of winter depression: behavioral and neuroendocrine effects of the 5-HT(1A) receptor partial agonist ipsapirone in patients with seasonal affective disorder and healthy control subjects. 1035 79


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