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)

GABA(B) receptor-mediated responses were investigated in human and rat neocortical neurones in vitro by using intracellular recording. Human epileptogenic tissue and cortex from rats were compared for differences related to the cellular mechanisms of hyperexcitability. In both tissues, single stimuli of various intensities were used to compare basic properties of excitatory and inhibitory postsynaptic potentials (EPSP, IPSP). Paired stimuli, causing a decrease of a second IPSP, were used as an index of presynaptic activation of GABA(B) receptors. In neocortical neurones of rats, increasing intensities of stimulation elicited at low intensities (6-8 V) a fairly pure EPSP which was curtailed at higher stimulus intensities (10-14 V) by a GABA(A) receptor mediated IPSP (IPSP(A)). In all rat neocortical neurones the IPSP(A) was followed by a late inhibitory component (IPSP(B), time to peak about 150 ms) which was eliminated by the GABA(B) receptor antagonists CGP 35348 or CGP 55845A. On average, paired stimuli reduced the amplitude of a second IPSP(A) to 57% of the first (in the presence of 10 microM CNQX and 20 microM D-APV). Paired-pulse depression was only antagonized by CGP 55845A, but not by CGP 35348. The magnitude and time course of paired-pulse depression was markedly enhanced at lower temperatures. In human cortical neurones obtained following epilepsy surgery only low intensity stimuli (4 V) elicited EPSPs. Intermediate to higher stimulus intensities (8-10 V) elicited often all-or-none depolarization shifts or prolonged and increased EPSPs. Few neurones exhibited a sequence of EPSP and IPSPs comparable to that observed in rat neurones. Application of CGP 55845A caused little change in excitability near 150 ms, indicating that the IPSP(B) is weak. Paired-pulse depression of inhibition was small in most neurones, the second IPSPA was reduced to 82.8% of the first at a 500 ms interval (n = 6). Only two neurones exhibited a paired-pulse depression comparable to rat neurones. The consequences of GABA receptor-mediated paired-pulse depression on neuronal synchronisation are discussed towards the different cellular mechanisms of focal and bilateral synchronous epilepsies.
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PMID:GABA(B) receptor-mediated effects in human and rat neocortical neurones in vitro. 1058 91

An important but poorly understood event associated with ischemia is anoxic depolarization (AD), a sudden and profound depolarization of neurons and glia in cortical and subcortical gray matter. Leao first measured the AD as a wave of electrical silence moving across the cerebral cortex in 1947 and noted its similarity to spreading depression (SD). SD is harmless when coursing through normoxic cortical tissue as during migraine aura. However for 3-4 h following focal ischemia, the additional metabolic stress arising from recurring SD in the penumbra expands the ischemic core, so SD blockade is potentially beneficial therapeutically. In the present study, we measured intrinsic optical signals (IOSs) to monitor anoxic depolarization in submerged rat neocortical slices during O2/glucose deprivation (OGD). After approximately 6 min of OGD, the AD was imaged as a focal increase in light transmittance which then propagated across neocortical gray at approximately 2 mm/min. Although the slice was globally stressed, the AD always initiated focally, sometimes at multiple sites. Its propagation was coincident with a transient negative shift in the extracellular potential, the electrical signature of AD. Acute damage to neocortex (measured as a delayed decrease in LT and as a loss of the evoked field potential) followed only where the AD had propagated, so it is the combined metabolic demands of AD and OGD that acutely damages all layers of the neocortex. Glutamate receptor antagonists (2 mM kynurenate or 25 microM AP-5/10 microM CNQX) did not block AD initiation, slow its propagation or prevent post-AD damage. This study shows that acute ischemic damage is greatly exacerberated by AD during metabolic stress and that glutamate receptor antagonists are not protective. Using this slice model, therapeutically tolerable drugs that block the AD and SD can be investigated.
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PMID:Anoxic depolarization mediates acute damage independent of glutamate in neocortical brain slices. 1123 96

Kainate receptor activation depresses synaptic release of neurotransmitter at a number of synapses in the CNS. The mechanism underlying this depression is controversial, and both ionotropic and metabotropic mechanisms have been suggested. We report here that the AMPA/kainate receptor agonists domoate (DA) and kainate (KA) cause a presynaptic depression of glutamatergic transmission at CA3-->CA1 synapses in the hippocampus, which is not blocked by the AMPA receptor antagonist GYKI 53655 but is blocked by the AMPA/KA receptor antagonist CNQX. Neither a blockade of interneuronal discharge nor antagonists of several neuromodulators affect the depression, suggesting that it is not the result of indirect excitation and subsequent release of a neuromodulator. Presynaptic depolarization, achieved via increasing extracellular K(+), caused a depression of the presynaptic fiber volley and an increase in the frequency of miniature EPSCs. Neither effect was observed with DA, suggesting that DA does not depress transmission via a presynaptic depolarization. However, the effects of DA were abolished by the G-protein inhibitors N-ethylmaleimide and pertussis toxin. These results suggest that KA receptor activation depresses synaptic transmission at this synapse via a direct, presynaptic, metabotropic action.
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PMID:Kainate receptors depress excitatory synaptic transmission at CA3-->CA1 synapses in the hippocampus via a direct presynaptic action. 1131 79

Unitary IPSCs elicited by fast-spiking (FS) interneurons in layer V pyramidal cells of the neocortex were studied by means of dual whole-cell recordings in acute slices. FS to pyramidal cell unitary IPSCs were depressed by (RS)-S-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) (ATPA), a kainate (KA) receptor agonist, and by the endogenous agonist l-glutamate in the presence of AMPA, NMDA, mGluR, and GABA(B) receptor antagonists. This effect was accompanied by an increase in failure rate of synaptic transmission, in the coefficient of variation, and in the paired pulse ratio, indicating a presynaptic origin of the IPSC depression. Pairing the activation of the presynaptic neuron with a depolarization of the postsynaptic cell mimicked the decrease of unitary IPSCs, and this effect persisted when postsynaptic sodium action potentials were blocked with the local anesthetic QX314. The effects of ATPA, glutamate, and of the pairing protocol were almost totally blocked by CNQX. These data suggest that KA receptors located on presynaptic FS cell terminals decrease the release of GABA and can be activated by glutamate released from the somatodendritic compartment of the postsynaptic pyramidal cells.
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PMID:Kainate receptors regulate unitary IPSCs elicited in pyramidal cells by fast-spiking interneurons in the neocortex. 1131 83

In the guinea pig, unilateral labyrinthectomy causes an immediate and severe depression of the spontaneous activity of the ipsilateral central vestibular neurons, which subsequently recovers completely within one week. A possible underlying mechanism could be an increase in the endogenous activity of the neurons deprived of their labyrinthine input. Here, we addressed this hypothesis. The endogenous activity of the neurons was assessed by their spontaneous activity recorded extracellularly in brainstem slices in the presence of a cocktail of neurotransmitter blockers (CNQX, D-APV, bicuculline and strychnine) which freed them from their main synaptic influences. The left medial vestibular nucleus (MVN) was explored in a very systematic way and strict methodological precautions were taken in order to validate comparisons between the numbers of spontaneously active neurons recorded in the MVN of distinct slices. In the presence of neurotransmitter antagonists, the mean number of spontaneously active neurons detected in a single MVN increased dramatically from 9.5 in slices from control guinea pigs to 26.3 in slices from animals labyrinthectomized on the left side one week beforehand. The mean firing rate of the recorded neurons also increased from 7.5 +/- 5.6 spikes/s in slices from control animals to 12.3 +/- 7.6 spikes/s in slices from guinea pigs labyrinthectomized one week beforehand. These results show that deprivation of the vestibular neurons of their labyrinthine input caused a change in the deprived neurons themselves. They suggest that an increase in pacemaker activity might be a factor responsible for the restoration of spontaneous activity in the vestibular neurons after labyrinthectomy.
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PMID:Modification of the pacemaker activity of vestibular neurons in brainstem slices during vestibular compensation in the guinea pig. 1145 26

Therapeutic uses of Hypericum extracts have been demonstrated as safe and effective in treating mild to moderate depression in numerous clinical trials. To date, however, no definitive statements on their mode of action can be made, and little information on their electrophysiological effects is available. The present communication summarises the results of our efforts directed towards clarifying the effects of an ethanolic Hypericum extract (HYP) and its hydrosoluble fraction (HYPWS), and two of its constituents hypericin and hyperforin on electrically evoked population spikes in guinea pig hippocampal slices. In higher concentrations (>10 microM), the two extract constituents tested revealed inhibitory effects only, whereas concentration-dependent (between 10(-6) to 10(-4) g/l) excitatory effects were observed for HYP and HYPWS. The excitatory effects were strongly amplified by the GABA(B) antagonist phaclofen, whereas the effects of bicucullin, a GABA(A) antagonist, were marginal. The excitations were completely blocked by the AMPA antagonist CNQX, but not by the NMDA antagonists APV and MK801 or the L-type calcium-channel blocker verapamil. This kind of excitatory effect on the hippocampus is unknown in other antidepressants and; indeed, many of the latter reduce neuronal excitability. We conclude, therefore, that the mechanisms involved in the antidepressant activity of Hypericum extracts are different from those of conventional antidepressants, and that identifying their excitatory components may facilitate their more rational standardisation.
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PMID:Effects of Hypericum perforatum L. on evoked potentials in guinea pig hippocampal slices. 1151 83

Excitatory postsynaptic currents (EPSCs) in parasympathetic preganglionic neurons (PGNs) were examined using the whole cell patch-clamp recording technique in L6 and S1 spinal cord slices from neonatal rats (6-16 days old). PGNs were identified by labeling with retrograde axonal transport of a fluorescent dye (Fast Blue) injected into the intraperitoneal space 3-7 days before the experiment. Synaptic responses were evoked in PGNs by field stimulation of the lateral funiculus (LF) in the presence of bicuculline methiodide (10 microM) and strychnine (1 microM). In approximately 40% of the cells (total, 100), single-shock electrical stimulation of the LF elicited short, relatively constant latency [3.0 +/- 0.1 (SE) ms] fast EPSCs consistent with a monosynaptic pathway. The remainder of the cells did not respond to stimulation. At low intensities of stimulation, the EPSCs often occurred in an all-or-none manner, indicating that they were mediated by a single axonal input. Most cells (n = 33) exhibited only fast EPSCs (type 1), but some cells (n = 8) had fast EPSCs with longer, more variable latency polysynaptic EPSCs superimposed on a slow inward current (type 2). Type 1 fast synaptic EPSCs were pharmacologically dissected into two components: a transient component that was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5 microM), a non-NMDA glutamatergic antagonist, and a slow decaying component that was blocked by 2-amino-5-phosphonovalerate (APV, 50 microM), a NMDA antagonist. Type 2 polysynaptic currents were reduced by 5 microM CNQX and completely blocked by combined application of 5 microM CNQX and 50 microM APV. The fast monosynaptic component of type 1 EPSCs had a linear current-voltage relationship and reversed at a membrane potential of 5.0 +/- 5.9 mV (n = 5), whereas the slow component exhibited a negative slope conductance at holding potentials greater than -20 mV. The type 1, fast synaptic EPSCs had a time to peak of 1.4 +/- 0.1 ms and exhibited a biexponential decay (time constants, 5.7 +/- 0.6 and 38.8 +/- 4.0 ms). In the majority of PGNs (n = 11 of 15 cells), EPSCs evoked by electrical stimulation of LF exhibited paired-pulse inhibition (range; 25-33% depression) at interstimulus intervals ranging from 50 to 120 ms. These results indicate that PGNs receive monosynaptic and polysynaptic glutamatergic excitatory inputs from axons in the lateral funiculus.
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PMID:Excitatory synaptic currents in lumbosacral parasympathetic preganglionic neurons elicited from the lateral funiculus. 1160 Jun 22

In order to clarify the functional role of glutamate receptors of the gracile nucleus neurons in rats with nerve injury-induced hyperalgesia, pharmacological, electrophysiological and in situ hybridization techniques were used in rats with chronic constriction nerve injury (CCI) of the sciatic nerve. A total of 54 wide dynamic range neurons were recorded from the gracile nucleus in the rats with CCI. Mechanical evoked responses were significantly depressed following application of AMPA receptor antagonist, CNQX, with noxious and non-noxious responses being similarly affected. AP-5, an NMDA receptor antagonist, induced depression of the pressure-evoked response only after application of the 1-microM concentration of this drug. The size of the receptive fields was significantly decreased after CNQX, but not MK-801 or AP-5, application. Afterdischarge was significantly depressed following the application of CNQX (1000 microM). The expression of ionotropic glutamate receptor subunit mRNAs in the gracile nucleus was studied using the in situ hybridization technique. The signals for NMDA subunits, NR2A, -2B and -2C, in the gracile nucleus neurons were not prominent, suggesting a low level expression of functional NMDA receptor complex. AMPA receptor subunits GluR1, -R2, -R3 and -R4 mRNAs were expressed in a large number of gracile nucleus neurons. These data are consistent with the pharmacological results that AMPA receptor antagonists depressed nociceptive neuronal activity, but NMDA receptor antagonists showed limited effects. These results suggest that the ionotropic glutamate receptors, i.e. the AMPA and NMDA receptors, are differentially involved in modulation of the wide dynamic range neuronal activity in the gracile nucleus following peripheral nerve injury.
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PMID:Involvement of glutamate receptors on hyperexcitability of wide dynamic range neurons in the gracile nucleus of the rats with experimental mononeuropathy. 1179 Apr 78

Extracellular field potentials, evoked by stimulation of the cortico-NAcc border, were recorded from the nucleus accumbens (NAcc) in horizontal slices of rat ventral forebrain. The peak amplitude of the population spike/excitatory postsynaptic potential complex (PEC, N2 component) was reduced by 78+/-2% ( n=44) by the antagonist of AMPA-type glutamate receptors, 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX, 10 microM). Dopamine (100 microM) reversibly depressed the peak amplitude of the PEC by 40+/-3% ( n=44). The GABA(A) receptor antagonists picrotoxin (10, 30 microM), or bicuculline methiodide (BMI, 20 microM), significantly reduced the PEC depression caused by dopamine (100 microM) to 9+/-3% ( n=20), 12+/-7% ( n=8) and 13+/-3% ( n=4) of control respectively, which, in the case of BMI, was reversible on washout of BMI. In slices with the frontal cortex removed (decorticated), dopamine (100 microM) was without effect on the PEC ( n=14). In contrast, the inhibition of the PEC by adenosine (by 40+/-9% in control, n=4), which was blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 200 nM), was unaffected by picrotoxin (50 microM, n=4), and persisted in decorticated slices, albeit increased to 88+/-2% ( n=4) of control. These results indicate that the depression of the cortico-NAcc synaptic transmission by dopamine in this preparation is due to an action in frontal, possibly piriform, cortex, which may involve modulation of intracortical GABAergic circuitry. In contrast, depression by adenosine is consistent with a presynaptic action via A1 receptors on intra-NAcc glutamate-releasing terminals, although there may be an additional action of adenosine within the cortex that also influences the cortico-NAcc PEC.
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PMID:Depression of excitatory cortico-nucleus accumbens synaptic transmission in rat brain slices by dopamine, but not adenosine, depends upon intracortical mechanisms. 1181 Jan 49

Neurons in the nucleus laminaris detect the coincidence of binaural signals, and are the first neurons to calculate the interaural time difference for the sound source localization in birds. In this paper, we have studied contributions of synaptic depression to the coincidence detection in the nucleus laminaris in a slice preparation of the chick embryo (E16-18), using the whole-cell patch recording technique. Under voltage clamp, EPSCs decreased progressively in their amplitude during the course of tetanic stimuli. This synaptic depression was primarily ascribed to the reduction of transmitter release from the presynaptic terminal, because the depression was decreased by reducing transmitter release with 2.5 microm Cd2+ but was not affected by reducing desensitization of postsynaptic AMPA receptors with 20 microm cyclothiazide. Under current clamp, trains of 10 stimuli of 100 Hz were applied bilaterally with changing the time intervals systematically between both sides. Response window, defined as the time interval corresponding to the half-maximum firing probability, was narrowed during the course of the stimulus train, and this occurred in parallel with a decrease in the EPSP amplitude. In addition, the reduction of the EPSP amplitude due to 2.5 microm Cd2+ or 2 microm CNQX improved the accuracy of coincidence detection. These results indicate that the synaptic depression may improve the coincidence detection in the chick laminaris neurons.
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PMID:Synaptic depression improves coincidence detection in the nucleus laminaris in brainstem slices of the chick embryo. 1191 58


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