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ABSTRACT: In the striatum, dopamine generates arachidonic acid (AA) and induces synaptic depression. Here, we report that Na+ channels are a target for AA in both cultured and acutely isolated striatal neurons. AA depressed veratrine-induced Na+ influx and neurotransmitter release. Whole-cell voltage clamp revealed that peak Na+ currents are depressed, and steady-state inactivation shifts -15 mV in the presence of AA. Furthermore, inactivation was accelerated, and recovery from inactivation was delayed. These actions of AA were not produced by AA metabolites or protein kinase C activation. In addition, AA reduced both the amplitude and frequency of action potentials and depressed spontaneous inhibitory postsynaptic currents without affecting miniature inhibitory postsynaptic currents. These data suggest that AA modulates presynaptic, Na(+)-dependent action potentials, thereby contributing to striatal synaptic depression.
Neuron 11/1993; 11(4):633-44. · 14.74 Impact Factor
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ABSTRACT: Voltage-activated high- and low-threshold Ca2+ currents were studied using whole-cell voltage-clamp techniques and fura-2 fluorescence measurements of intracellular Ca2+ in neurons acutely isolated from rat neostriatum. High-threshold Ca2+ currents activated around -40 mV and were present in at least 95% of neostriatal neurons. The maximum current, 736 +/- 44 pA (mean +/- SEM, n = 141), was observed around 0 mV. In 70% of neurons, high-threshold Ca2+ currents exhibited both inactivating and noninactivating components. The majority of the high-threshold Ca2+ currents appeared to belong neither to the "L-type" nor the "N-type" classification, since omega-conotoxin (5 microM) decreased this current by only 29% and nimodipine (10 microM) decreased the noninactivating component of this current by only 17%. A low-threshold transient (T-type) Ca2+ current was observed in 40% of neurons. When both T-type and high-threshold Ca2+ currents were present, their maximum amplitudes were 78 +/- 7 pA and 800 +/- 57 pA, respectively (mean +/- SEM, n = 58). At a holding potential of -100 mV, the T-type Ca2+ current activated around -60 mV, with maximum current near -40 mV. Steady-state inactivation of the T-type Ca2+ current was observed at holding potentials positive to -125 mV, and the current was half-inactivated at -88 mV. Recovery from inactivation to 90% of maximum occurred within 800 msec. Mn2+ or Co2+ (3 mM) blocked both high-threshold and T-type Ca2+ currents, whereas Cd2+ (25 microM) or verapamil (50 microM and 150 microM) preferentially blocked high-threshold over T-type Ca2+ currents. In response to depolarization by 50 mM K+, fura-2 fluorescence measurements showed increased intracellular Ca2+ in both the soma and the proximal dendrites of neostriatal neurons that was markedly reduced by 25 microM Cd2+. These findings suggest that high-threshold Ca channels are present in both the soma and proximal dendrites of neostriatal neurons.
Journal of Neuroscience 04/1993; 13(3):1244-57. · 7.11 Impact Factor
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ABSTRACT: Slow inward currents modulate neuronal firing patterns and may generate depolarizing afterpotentials (DAPs). We report a novel, slow Na+ current (INaS) in striatal and hippocampal neurons that can generate DAPs. INaS activated at depolarizations greater than -40 mV, was tetrodotoxin insensitive, and activated and deactivated slowly over hundreds of milliseconds. INaS was dependent upon extracellular Na+, but was not affected by 0 mM extracellular Ca2+ or by Ca2+ channel blockers (Mn2+, Cd2+, or Co2+). A tetrodotoxin-insensitive, Na(+)-dependent plateau potential that was likely generated by INaS was shown to underlie DAPs during intracellular recordings from hippocampal CA1 pyramidal neurons. Membrane depolarizations and DAPs generated by INaS may contribute to alterations in neuronal firing and epileptiform bursting.
Neuron 04/1993; 10(3):543-52. · 14.74 Impact Factor
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ABSTRACT: Tetrodotoxin reduced N-methyl-D-aspartate (NMDA)-evoked release of adenosine by 35% but virtually abolished [3H]norepinephrine release. Although [3H]norepinephrine release from rat cortical slices evoked by 500 microM NMDA was abolished by 1.2 mM Mg++, which produces a voltage-sensitive, uncompetitive block of NMDA-channels, adenosine release was increased in the presence of Mg++. Partial depolarization with 12 mM K+ relieved the Mg++ block of 500 microM NMDA-evoked [3H]norepinephrine release but did not affect adenosine release, indicating that a Mg++ requirement for the adenosine release process per se cannot account for this discrepancy. NMDA was 33 times more potent in releasing adenosine than [3H]norepinephrine. At submaximal concentrations of NMDA (10 and 20 microM), adenosine release was augmented in Mg+(+)-free medium. Although a high concentration of the uncompetitive NMDA antagonist MK-801 [(+)-5-methyl-10,11,dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine maleate] (3 microM) blocked NMDA-evoked release of [3H]norepinephrine and adenosine, a lower concentration (300 nM) decreased NMDA-evoked [3H]norepinephrine release by 66% without affecting adenosine release. These findings suggest that maximal adenosine release occurs when relatively few NMDA receptors are activated, raising the possibility that spare receptors exist for NMDA-evoked adenosine release. Rather than acting as a protectant against excessive NMDA excitation, released adenosine might provide an inhibitory threshold which must be overcome for NMDA-mediated neurotransmission to proceed.
Journal of Pharmacology and Experimental Therapeutics 11/1990; 255(1):174-81. · 3.83 Impact Factor
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ABSTRACT: L-Glutamate (10 microM-1 mM) released endogenous adenosine from rat cortical synaptosomes. Studies with excitatory amino acid antagonists, (+)-5-methyl-16,11,dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), 6,7-dinitroquinoxaline-2,3-dione (DNQX), Mg2+, and agonists N-methyl-D-aspartate (NMDA), kainate, and quisqualate, indicated that this release was not receptor mediated. D,L-2-Amino-4-phosphonobutanoic acid (APB) also did not affect glutamate-evoked adenosine release. Inhibition of glutamate uptake by dihydrokainate or replacement of extracellular Na+ blocked glutamate-evoked adenosine release. D-aspartate, which is a substrate for the glutamate transporter but is not metabolized, also released adenosine, suggesting that release was due to amino acid transport and not to its subsequent metabolism. D-Glutamate, a relatively poor substrate for the transporter, was correspondingly less potent than L-glutamate at releasing adenosine. Glutamate-evoked adenosine release was not Ca2+ dependent or tetrodotoxin sensitive and did not appear to occur on the bidirectional nucleoside transporter. Inhibition of ecto-5'-nucleotidase virtually abolished glutamate-evoked adenosine release, indicating that adenosine was derived from extracellular metabolism of released nucleotide(s). However, L-glutamate did not release ATP and did not appear to release cyclic AMP. Therefore, transport of glutamate into presynaptic terminals releases some other nucleotide which is converted extracellularly to adenosine. This adenosine could act at P1-purinoceptors to modulate glutamatergic neurotransmission.
Journal of Neurochemistry 06/1990; 54(5):1716-24. · 4.06 Impact Factor
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ABSTRACT: N-Methyl-D-aspartate, kainate, and quisqualate released endogenous adenosine from superfused slices of rat parietal cortex. N-Methyl-D-aspartate-evoked adenosine release was blocked by D,L-2-amino-5-phosphono-valeric acid and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), indicating that it was receptor-mediated, although it did not show the expected potentiation in the absence of Mg2+. In contrast, N-methyl-D-aspartate-evoked release of [3H]noradrenaline from the same slices was markedly potentiated in Mg2(+)-free medium. Therefore, the lack of Mg2+ modulation of N-methyl-D-aspartate-evoked adenosine release was not due to depolarization-induced alleviation of the Mg2+ block in the slices. Kainate-evoked adenosine release was diminished by the non-specific excitatory amino acid antagonist, gamma-D-glutamyl-glycine, and kainate- and quisqualate-evoked adenosine release was diminished by 6,7-dinitroquinoxaline-2,3-dione, indicating that these agonists release adenosine by acting at non-N-methyl-D-aspartate receptors. Tetrodotoxin decreased N-methyl-D-aspartate- and kainate-evoked adenosine release by 40% and 19% respectively, indicating that release was mediated in part by propagated action potentials in the slices. Total release of adenosine by N-methyl-D-aspartate, kainate or quisqualate was not diminished in the absence of Ca2+. A second exposure to kainate following restoration of Ca2+ to slices previously depolarized in the absence of Ca2+ resulted in an amount of adenosine release equal to an initial release by slices in the presence of Ca2+, a result suggesting the presence of separate Ca2(+)-dependent and Ca2(+)-independent pools of adenosine. The present experiments demonstrate that activation of all three major subtypes of excitatory amino acid receptors in the cortex releases adenosine, possibly from separate Ca2(+)-dependent and -independent pools. Adenosine released from the cortex following excitatory amino acid stimulation may, by acting at inhibitory P1 purinoceptors, diminish excitatory neurotransmission and protect against excitotoxicity.
Neuroscience 02/1990; 39(2):441-50. · 3.38 Impact Factor
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ABSTRACT: K+ and glutamate released endogenous adenosine from superfused slices of rat parietal cortex. The absence of Ca2+ markedly diminished K+- but not glutamate-evoked adenosine release. Tetrodotoxin decreased K+- and glutamate-evoked adenosine release by 40 and 20%, respectively, indicating that release was mediated in part by propagated action potentials in the slices. Inhibition of ecto-5'-nucleotidase by alpha,beta-methylene ADP and GMP decreased basal release of adenosine by 40%, indicating that part of the adenosine was derived from the extracellular metabolism of released nucleotide. In contrast, inhibition of ecto-5'-nucleotidase did not affect release evoked by K+ or glutamate, suggesting that adenosine was released as such. Inhibition of glutamate uptake by dihydrokainate potentiated glutamate-evoked release of adenosine. Glutamate-evoked adenosine release was diminished 50 and 55% by the N-methyl-D-aspartate (NMDA) receptor antagonists, DL-2-amino-5-phosphonovaleric acid and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), respectively. The remaining release in the presence of MK-801 was diminished a further 66% by the non-NMDA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione, suggesting that both NMDA and non-NMDA receptors were involved in glutamate-evoked adenosine release. Surprisingly, K+-evoked adenosine release was also diminished about 30% by NMDA antagonists, suggesting that K+-evoked adenosine release may be partly mediated indirectly through the release of an excitatory amino acid acting at NMDA receptors.
Journal of Neurochemistry 02/1990; 54(1):256-65. · 4.06 Impact Factor
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ABSTRACT: Release of endogenous adenosine from rat cortical slices was determined in response to depolarization by 30 mM K+ and by exposure to glutamate. K+ and glutamate both released adenosine. Glutamate-evoked release was decreased by approximately 50% in the presence of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonovaleric acid (APV). The adenosine released by glutamate could modulate neurotransmission, and may have a protective effect in pathologic conditions of excess excitation involving glutamate.
Brain Research 02/1989; 478(1):149-51. · 2.73 Impact Factor
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ABSTRACT: The effect of intrathecal pretreatment with pertussis toxin on the spinal antinociceptive effect of morphine, noradrenaline and L-baclofen was examined in rats implanted with chronic indwelling cannulas. Pretreatment with 0.25-0.75 micrograms pertussis toxin for 2-7 days inhibited antinociception produced by intrathecal injection of all three agents in the tail flick test. Inhibition also occurred in the hot plate test, but was less pronounced than in the tail flick test. When doses of the three agents giving similar levels of antinociception were compared in a single group, the degree of inhibition of antinociception was comparable. Inhibition of the effect of noradrenaline was observed up to 14 days following pretreatment. The sensitivity of spinal antinociception to pertussis toxin suggests involvement of a guanine nucleotide regulatory protein in spinal actions of morphine, noradrenaline and L-baclofen. There is support in the literature for the additional involvement of adenylate cyclase in the action of morphine and noradrenaline but not of baclofen.
European Journal of Pharmacology 02/1988; 146(1):65-72. · 2.52 Impact Factor
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ABSTRACT: N-Methyl-d-aspartate, kainate, and quisqualate released endogenous adenosine from superfused slices of rat parietal cortex.N-Methyl-d-aspartate-evoked adenosine release was blocked byd,1-2-amino-5-phosphono-valeric acid and ( + )-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), indicating that it was receptor-mediated, although it did not show the expected potentiation in the absence of Mg2+. In contrast,N-methyl-d-aspartate-evoked release of [3H]noradrenaline from the same slices was markedly potentiated in Mg2+-free medium. Therefore, the lack of Mg2+ modulation ofN-methyl-d-aspartate-evoked adenosine release was not due to depolarization-induced alleviation of the Mg2+ block in the slices. Kainate-evoked adenosine release was diminished by the non-specific excitatory amino acid antagonist, γ-d-glutamyl-glycine, and kainate- and quisqualate-evoked adenosine release was diminished by 6,7-dinitroquinoxaline-2,3-dione, indicating that these agonists release adenosine by acting atnon-N-methyl-d-aspartate receptors. Tetrodotoxin decreasedN-methyl-d-aspartate- and kainate-evoked adenosine release by 40% and 19% respectively, indicating that release was mediated in part by propagated action potentials in the slices. Total release of adenosine byN-methyl-d-aspartate, kainate or quisqualate was not diminished in the absence of Ca2+. A second exposure to kainate following restoration of Ca2+ to slices previously depolarized in the absence of Ca2+resulted in an amount of adenosine release equal to an initial release by slices in the presence of Ca2+, a result suggesting the presence of separate Ca2+-dependent and Ca2+-independent pools of adenosine.The present experiments demonstrate that activation of all three major subtypes of excitatory amino acid receptors in the cortex releases adenosine, possibly from separate Ca2+-dependent and -independent pools. Adenosine released from the cortex following excitatory amino acid stimulation may, by acting at inhibitory P1 purinoceptors, diminish excitatory neurotransmission and protect against excitotoxicity.
Neuroscience.
