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      • HARVEST
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      Effects of selected transmitters on free cytosolic calcium concentration and pyruvate dehydrogenation in primary cultures of mouse astrocytes

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      Date
      1996-01-01
      Author
      Chen, Ye
      Type
      Thesis
      Degree Level
      Doctoral
      Metadata
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      Abstract
      To study the effects of neurotransmitters on [Ca2+]i and oxidative metabolism of pyruvate, selected adrenergic, serotonergic, purinergic and peptidergic agonists were chosen. Experiments were conducted using the fluorescent calcium indicator, indo-1/AM, to examine changes in [Ca2+,/sup>]i and [1-14C] pyruvate to measure rates of labeled CO2 formation from pyruvate dehydrogenation. The adrenergic agonist noradrenaline induced an increase in [Ca2+]i via activation of both á1 and á2 receptors as both phenylephrine (á1 agonist) and clonidine (á2 agonist) caused an elevation in [Ca2+]i level. The increase in [Ca2+]i evoked by either noradrenaline or phenylephrine was inhibited by inclusion of phentolamine (a nonspecific á-antagonist). Yohimbine, an á2-antagonist, inhibited both noradrenaline- and clonidine-evoked increases in [Ca2+]i, indicating the existence of a population of á2-adrenoceptors in cultured astrocytes. Noradrenaline also enhanced dehydrogenation of pyruvate to acetyl-CoA. Clonidine exerted a stimulation on pyruvate dehydrogenation and there was a tendency towards a small stimulation by phenylephrine. In contrast, CO2 formation was not increased when the potassium concentration was raised above 5 mM. Noradrenaline-induced stimulation of flux from pyruvate to acetylCoA was abolished in the absence of extracellular calcium (combined with an elevation of the magnesium concentration or a calcium chelator, EGTA), suggesting that the effect is calcium-dependent. Exposure to dexmedetomidine, a highly specific á2-adrenergic agonist, led to a biphasic increase in [Ca2+]i and in pyruvate oxidation. The effect was inhibited both by yohimbine and idazoxan. Chronic treatment with 1 mM lithium chloride decreased noradrenaline-induced increase in [Ca2+,/sup>]i. This is in agreement with the assumption that lithium impairs the turnover in the inositol phosphate (IP) cycle. Serotonin caused an increase of [Ca2+]i in concentrations between 10 pM and 10 ìM in dibutyryl cyclic adenosine 3',5'-monophosphate (dBcAMP) treated astrocytes by stimulating 5HT2C and/or 5-HT2A receptors. Micromolar concentrations of serotonin were required for activation of the 5-HT2A receptor, whereas low nanomolar concentrations stimulated the 5-HT2C receptor. Fluoxetine, an antidepressant acting like 5-HT, exerted an agonist effect on [Ca2+]i in astrocytes. Adenosine and guanosine, purinergic agonists, evoked significant increases in [Ca2+]i, an effect that was not blocked by P1 antagonists. Arginine vasopressin (AVP) induced increases in [Ca2+]i which could be abolished by a V1-selective antagonist but not by removal of extracellular Ca2+. However, AVP failed to affect pyruvate oxidation in astrocytes.
      Degree
      Doctor of Philosophy (Ph.D.)
      Department
      Pharmacology
      Program
      Pharmacology
      Committee
      Hertz, Leif
      Copyright Date
      January 1996
      URI
      http://hdl.handle.net/10388/etd-10212004-000121
      Subject
      pharmacology
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      • Graduate Theses and Dissertations
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