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)

Many neuromodulators inhibit N-type Ca2+ currents via G protein-coupled pathways in acutely isolated superior cervical ganglion (SCG) neurons. Less is known about which neuromodulators affect release of norepinephrine (NE) at varicosities and terminals of these neurons. To address this question, we used carbon fiber amperometry to measure catecholamine secretion evoked by electrical stimulation at presumed sites of high terminal density in cultures of SCG neurons. The pharmacological properties of action potential-evoked NE release paralleled those of N-type Ca2+ channels: Release was completely blocked by Cd2+ or omega-conotoxin GVIA, reduced 50% by 10 microM NE or 62% by 2 microM UK-14,304, an alpha2-adrenergic agonist, and reduced 63% by 10 microM oxotremorine M (Oxo-M), a muscarinic agonist. Consistent with action at M2 or M4 receptor subtypes, Oxo-M could be antagonized by 10 microM muscarinic antagonists methoctramine and tropicamide but not by pirenzepine. After overnight incubation with pertussis toxin, inhibition by UK-14,304 and Oxo-M was much reduced. Other neuromodulators known to inhibit Ca2+ channels in these cells, including adenosine, prostaglandin E2, somatostatin, and secretin, also depressed secretion by 34-44%. In cultures treated with omega-conotoxin GVIA, secretion dependent on L-type Ca2+ channels was evoked with long exposure to high K+ Ringer's solution. This secretion was not sensitive to UK-14,304 or Oxo-M. Evidently, many neuromodulators act on the secretory terminals of SCG neurons, and the depression of NE release at terminals closely parallels the membrane-delimited inhibition of N-type Ca2+ currents in the soma.
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PMID:Modulation by neurotransmitters of catecholamine secretion from sympathetic ganglion neurons detected by amperometry. 903 83

Veratridine blocks Na(+)-channel inactivation and causes a persistant Na(+)-influx. Exposure of hippocampal slices to 10 microM veratridine led to a failure of synaptic transmission, repetitive spreading depression (SD)-like depolarizations of increasing duration, loss of Ca(+)-homeostasis, a large reduction of membrane potential, spongious edema and metabolic failure. Normalization of the amplitude of the negative DC shift evoked by high K+ ACSF 80 min after veratridine exposure was taken as the primary endpoint for neuroprotection. Compounds whose mechanisms of action includes Na(+)-channel modulation were neuroprotective (IC50-values in microM): tetrodotoxin 0.017, verapamil 1.18, riluzole 1.95, lamotrigine > or = 10, and diphenylhydantoin 16.1. Both NMDA (MK-801 and PH) and non-NMDA (NBQX) excitatory amino acid antagonists were inactive, as were NOS-synthesis inhibitor (nitro-L-arginine and L-NAME) Ca(2+)-channel blockers (cadmium, nimodipine) and a K(+)-channel blocker (TEA). Lubeluzole significantly delayed in time before the slices became epileptic, postponed the first SD-like depolarization, allowed the slices to better recover their membrane potential after a larger number of SD-like DC depolarizations, preserved Ca2+ and energy homeostasis, and prevented the neurotoxic effects of veratridine (IC50-value 0.54 microM). A concentration of lubeluzole, which was 40 x higher than its IC50-value for neuroprotection against veratridine, had no effect on repetitive Na(+)-dependent action potentials induced by depolarizing current in normal ACSF. The ability of lubeluzole to prevent the pathological consequences of excessive Na(+)-influx, without altering normal Na(+)- channel function may be of benefit in stroke.
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PMID:Altered Na(+)-channel function as an in vitro model of the ischemic penumbra: action of lubeluzole and other neuroprotective drugs. 903 12

Previous studies have demonstrated that the voltage-dependent Ca2+ current recorded from the cell body of the crayfish abdominal motoneuron, F3, undergoes a long-term reduction as a result of increased impulse activity. The properties of the Ca2+ channels undergoing this long-term change were examined with the use of two-electrode voltage-clamp techniques. The Ca2+ current was activated at -50 to -40 mV and its amplitude was maximal at 0 mV (-135.0 +/- 25.8 nA, mean +/- SE, n = 14). The current-voltage relationship and the greater sensitivity of the Ca2+ channel to Cd2+ than Ni2+ indicated that Ca2+ influx occurs through high-voltage-activated (HVA) Ca2+ channels. Loose-patch recordings demonstrated that the Ca2+ current was generated by the membrane of the cell body. When Ba2+ was substituted for extracellular Ca2+, there was a 40% increase in the amplitude of the inward current and a negative shift of approximately 10 mV in the I-V relationship. Application of the P-type Ca2+ channel antagonist omega-agatoxin IVA (omega-AgTX IVA) produced a significant 33% (n = 6) reduction in the peak amplitude of the Ba2+ current, whereas neither the L-type Ca2+ channel antagonist nifedipine nor the N-type channel antagonist omega-conotoxin GVIA produced a reduction in the Ba2+ current. The voltage-dependent activation of this P-type (omega-AgTX-IVA-sensitive) Ca2+ channel was similar to previously identified P-type channels, but different from that of the non-P-type (omega-AgTX-IVA-resistant) Ca2+ channels. When Ca2+ currents were measured 6-7 h after an increase in impulse activity (5-Hz stimulation for 45-60 min), there was a 43% reduction in the amplitude of the P-type current, but no significant changes in the non-P-type current amplitude. These results demonstrate that at least two subtypes of HVA Ca2+ channels contribute to the macroscopic Ca2+ current observed in the cell body of this crayfish phasic motoneuron: one belongs to the previously described P-type Ca2+ channel and the other(s) does not belong to the N-, L-, or P-type Ca2+ channel. The long-term, Ca(2+)-dependent reduction in Ca2+ current previously demonstrated in motoneuron F3 is produced by the selective reduction of this P-type Ca2+ current. This activity-dependent reduction in the P-type Ca2+ current is likely involved in the long-term depression of transmitter release observed at the neuromuscular synapses of this motoneuron.
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PMID:Characterization of a P-type calcium current in a crayfish motoneuron and its selective modulation by impulse activity. 912 May 98

We have previously demonstrated that acute third ventricle injections of both Pb2+ and Cd2+ impair the dipsogenic response elicited by three different situations: dehydration and central cholinergic or angiotensinergic stimulation. beta-Adrenergic activation is part of the multifactorial integrated systems operating in drinking behavior control in the central nervous system. In the present study acute third ventricle injections of Pb2+ (3, 30 and 300 pmol/rat) or Cd2+ (0.3, 3 and 30 pmol/ rat) blocked the dipsogenic response induced by third ventricle injections of isoproterenol (ISO; 160 nmol/rat) in a dose-dependent manner. Normohydrated animals receiving ISO + NaAc (sodium acetate) or saline (controls) displayed a high water intake after 120 min (ISO+saline = 5.78 +/- 0.54 ml/100 g; ISO+NaAc = 6.00 +/- 0.6 ml/100 g). After the same period, animals receiving ISO but pretreated with PbAc at the highest dose employed (300 pmol/rat) drank 0.78 +/- 0.23 ml/100 g while those receiving ISO and pretreated with the highest dose of CdCl2 (30 pmol/rat) presented a water intake of 0.7 +/- 0.30 ml/100 g. Third ventricle injections of CdCl2 (3 nmol/rat) or PbAc (3 nmol/rat) did not modify food intake in rats deprived of food for 24 h. Thus, general central nervous system depression explaining the antidipsogenic action of the metals can be safely excluded. It is concluded that both Pb2+ and Cd2+ inhibit water intake induced by central beta-adrenergic stimulation.
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PMID:Lead (Pb2+) and cadmium (Cd2+) inhibit the dipsogenic action of central beta-adrenergic stimulation by isoproterenol. 924 42

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

Cadmium, a heavy metal, has been found to possess a potent toxic effect on liver and bone marrow. In the present study, attempts were made to understand whether or not any correlation existed between hepatic lipid peroxidation, glutathione S-transferase activity, reduced glutathione level and chromosome aberrations, micronucleus and mitotic index in bone marrow cells of Balb/C male mice. Cadmium chloride (2.5 mg/kg b.wt.), when administered subcutaneously for 7 alternate days, exerted duration-dependent toxic effects on hepatic biochemical and cytogenetic parameters of bone marrow. A shorter time interval (5 days) elicited no significant alteration in the case of biochemical parameters, but with the advancement of time (i.e. after 10 and 15 days) lipid peroxidation showed 102% (p < 0.001) elevation and after 15 days, glutathione S-transferase activity and reduced glutathione level decreased by 35%, (p < 0.001) and 32% (p < 0.001), respectively, from the control values with concomitant elevation of chromosomal aberrations (30%) and micronucleus (2.32%) but the mitotic index was inhibited by 1.26%. The results of our study, provided evidence of cadmium-induced duration-dependent depression of GSH-mediated GST-catalysed detoxication capacity of the host and that this was presumably related to the induction of chromosomal aberrations. The clastogenic efficacy of this heavy metal was thus evident from the study.
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PMID:Cadmium-induced alterations of hepatic lipid peroxidation, glutathione S-transferase activity and reduced glutathione level and their possible correlation with chromosomal aberration in mice: a time course study. 954 42

It is thought that galanin, a 29 amino acid neuropeptide, is involved in various neuronal functions, including the regulation of food intake and hormone release. Consistent with this idea, galanin receptors have been demonstrated throughout the brain, with high levels being observed in the hypothalamus. However, little is known about the mechanisms by which galanin elicits its actions in the brain. Therefore, we studied the effects of galanin and its analogs on synaptic transmission using an in vitro slice preparation of rat hypothalamus. In arcuate nucleus neurons, application of galanin resulted in an inhibition of evoked glutamatergic EPSCs and a decrease in paired-pulse depression, indicating a presynaptic action. The fragments galanin 1-16 and 1-15 produced a robust depression of synaptic transmission, whereas the fragment 3-29 produced a lesser degree of depression. The chimeric peptides C7, M15, M32, and M40, which have been reported to antagonize some actions of galanin, all produced varying degrees of depression of evoked EPSCs. In a minority of cases, C7, M15, and M40 antagonized the actions of galanin. Analysis of mEPSCs in the presence of TTX and Cd2+, or after application of alpha-latrotoxin, indicated a site of action for galanin downstream of Ca2+ entry. Thus, our data suggest that galanin acts via several subtypes of presynaptic receptors to depress synaptic transmission in the rat arcuate nucleus.
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PMID:Galanin receptor-mediated inhibition of glutamate release in the arcuate nucleus of the hypothalamus. 957 Jul 80

1. EPSCs were recorded under whole-cell voltage clamp at room temperature from Purkinje cells in slices of cerebellum from 12- to 14-day-old rats. EPSCs from individual climbing fibre (CF) inputs were identified on the basis of their large size, paired-pulse depression and all-or-none appearance in response to a graded stimulus. 2. Synaptic transmission was investigated over a wide range of experimentally imposed release probabilities by analysing fluctuations in the peak of the EPSC. Release probability was manipulated by altering the extracellular [Ca2+] and [Mg2+]. Quantal parameters were estimated from plots of coefficient of variation (CV) or variance against mean conductance by fitting a multinomial model that incorporated both spatial variation in quantal size and non-uniform release probability. This 'multiple-probability fluctuation' (MPF) analysis gave an estimate of 510 +/- 50 for the number of functional release sites (N) and a quantal size (q) of 0.5 +/- 0.03 nS (n = 6). 3. Control experiments, and simulations examining the effects of non-uniform release probability, indicate that MPF analysis provides a reliable estimate of quantal parameters. Direct measurement of quantal amplitudes in the presence of 5 mM Sr2+, which gave asynchronous release, yielded distributions with a mean quantal size of 0.55 +/- 0.01 nS and a CV of 0.37 +/- 0.01 (n = 4). Similar estimates of q were obtained in 2 mM Ca2+ when release probability was lowered with the calcium channel blocker Cd2+. The non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1 microM) reduced both the evoked current and the quantal size (estimated with MPF analysis) to a similar degree, but did not affect the estimate of N. 4. We used MPF analysis to identify those quantal parameters that change during frequency-dependent depression at climbing fibre-Purkinje cell synaptic connections. At low stimulation frequencies, the mean release probability (pr) was unusually high (0.90 +/- 0.03 at 0.033 Hz, n = 5), but as the frequency of stimulation was increased, pr fell dramatically (0.02 +/- 0.01 at 10 Hz, n = 4) with no apparent change in either q or N. This indicates that the observed 50-fold depression in EPSC amplitude is presynaptic in origin. 5. Presynaptic frequency-dependent depression was investigated with double-pulse and multiple-pulse protocols. EPSC recovery, following simultaneous release at practically all sites, was slow, being well fitted by the sum of two exponential functions (time constants of 0.35 +/- 0.09 and 3.2 +/- 0.4 s, n = 5). EPSC recovery following sustained stimulation was even slower. We propose that presynaptic depression at CF synapses reflects a slow recovery of release probability following release of each quantum of transmitter. 6. The large number of functional release sites, relatively large quantal size, and unusual dynamics of transmitter release at the CF synapse appear specialized to ensure highly reliable olivocerebellar transmission at low frequencies but to limit transmission at higher frequencies.
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PMID:Locus of frequency-dependent depression identified with multiple-probability fluctuation analysis at rat climbing fibre-Purkinje cell synapses. 966 Sep

In a cell line (C2D7) stably expressing the human N-type calcium channel encoded by the subunits alpha1B-a, beta1b, alpha2bdelta, we have analysed the Ca2+ currents produced by a range of action potential-like voltage protocols (APVPs). Such protocols consistently produced robust inward currents that could be eliminated by co-application of the Ca2+ channel blocking ions Cd2+ and La3+. The amplitude, latency to peak and area of the current produced by APVPs was dependent on the precise waveform of voltage protocol employed and the temperature. Short bursts of APVPs applied at 100 Hz produced a depression of the Ca2+ current amplitude which was dependent on the half-width of the APVP employed. In contrast, no frequency-dependent changes in the evoked current kinetics were detected. The amount of current depression seen during an 100 Hz 8 APVP burst was greatly enhanced by increasing the temperature from 22 to 37 degrees C. Alterations to the intracellular Ca2+ buffering capacity suggested that the Ca2+ current depression produced during an APVP train arose, at least in part, from a Ca2+-dependent inactivation of the human N-type Ca2+ channel.
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PMID:Electrophysiological characterisation of the human N-type Ca2+ channel II: activation and inactivation by physiological patterns of activity. 968 Feb 60

Synapses in the central nervous system undergo various short- and long-term changes in their strength, but it is often difficult to distinguish whether presynaptic or postsynaptic mechanisms are responsible for these changes. Using patch-clamp recording from giant synapses in the mouse auditory brainstem, we show here that short-term synaptic depression can be largely attributed to rapid depletion of a readily releasable pool of vesicles. Replenishment of this pool is highly dependent on the recent history of synaptic activity. High-frequency stimulation of presynaptic terminals significantly enhances the rate of replenishment. Broadening the presynaptic action potential with the potassium-channel blocker tetraethylammonium, which increases Ca2+ entry, further enhances the rate of replenishment. As this increase can be suppressed by the Ca2+-channel blocker Cd2+ or by the Ca2+ buffer EGTA, we conclude that Ca2+ influx through voltage-gated Ca2+ channels is the key signal that dynamically regulates the refilling of the releasable pool of synaptic vesicles in response to different patterns of inputs.
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PMID:High-frequency firing helps replenish the readily releasable pool of synaptic vesicles. 969 Apr 75


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