• Media type: E-Article
  • Title: Negative Effects of Tacrine (Tetrahydroaminoacridine) and Methoxytacrine on the Metabolism of Acetylcholine in Brain Slices Incubated Under Conditions Stimulating Neurotransmitter Release
  • Contributor: Tuček, Stanislav; Doležal, Vladimír
  • imprint: Wiley, 1991
  • Published in: Journal of Neurochemistry
  • Language: English
  • DOI: 10.1111/j.1471-4159.1991.tb11413.x
  • ISSN: 0022-3042; 1471-4159
  • Keywords: Cellular and Molecular Neuroscience ; Biochemistry
  • Origination:
  • Footnote:
  • Description: <jats:p><jats:bold>Abstract: </jats:bold> The effects of tacrine (1,2,3,4‐tetrahydro‐9‐aminoacridine) and 7‐methoxytacrine on the metabolism of brain acetylcholine were investigated in experiments in which acetylcholine turnover was stimulated by tissue depolarization or by 4‐aminopyridine. Rat cerebrocortical prisms were preincubated under “resting”conditions (Krebs‐Ringer buffer with 3 mmol/L K<jats:sup>+</jats:sup> and with paraoxon to inhibit cholinesterases) and then incubated in the presence of tacrine or methoxytacrine and of 50 mmol/L K<jats:sup>+</jats:sup>. Both drugs diminished the amount of acetylcholine released by depolarization and the amount of acetylcholine synthesized during incubation; in experiments in which [<jats:sup>14</jats:sup>]choline was present in the incubation medium simultaneously with tacrine or methoxytacrine, the drugs diminished the uptake of [<jats:sup>14</jats:sup>C]choline by the tissue and the amount of [<jats:sup>14</jats:sup>C]‐acetylcholine synthesized and released into the medium. In these experiments, it was not possible to distinguish whether the inhibitory effects of tacrine and methoxytacrine were primarily on the process of acetylcholine synthesis (particularly on the uptake of choline), or whether the drugs also acted directly on the process of neurotransmitter release. In subsequent experiments the prisms were preincubated with [<jats:sup>14</jats:sup>C]choline and only then subjected to a short depolarization in the presence of hemicholinium‐3 and tacrine or methoxytacrine. Both drugs severely inhibited the release of preformed [<jats:sup>14</jats:sup>C]acetylcholine and prevented the diminution of tissue [<jats:sup>14</jats:sup>C]acetylcholine stores. Methoxytacrine was also found to diminish the release of acetylcholine induced by 4‐aminopyridine while increasing the content of acetylcholine in the tissue. Tacrine and methoxytacrine had no effect on the activity of choline acetyltransferase (EC 2.3.1.6). Our observations indicate that, in addition to reducing the uptake of choline, tacrine and methoxytacrine inhibit the stimulated release of acetylcholine by acting directly on the process of neurotransmitter liberation. Most effects of tacrine and methoxytacrine were observed at a concentration of 100 μmol/L, but some were already apparent at a concentration of 10 μmol/L. The molecular mechanism of the direct inhibitory action of tacrine and methoxytacrine on the stimulated release of acetylcholine is not clear.</jats:p>