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. 1989 Dec;98(4):1127–1136. doi: 10.1111/j.1476-5381.1989.tb12656.x

The mechanism of tetrahydroaminoacridine-evoked release of endogenous 5-hydroxytryptamine and dopamine from rat brain tissue prisms.

T N Robinson 1, R J De Souza 1, A J Cross 1, A R Green 1
PMCID: PMC1854804  PMID: 2611486

Abstract

1 Tetrahydroaminoacridine (THA) is an acetylcholinesterase (AChE) inhibitor which may have a greater therapeutic effect in Alzheimer-type dementia (ATD) than other cholinergic agents. This suggests possible non-cholinergic properties. We have therefore studied the effects of THA on the release of endogenous 5-hydroxytryptamine (5-HT) from rat cortical prisms and dopamine from striatal prisms. 2 In the presence of K+ (1 mM), THA stimulated release of both 5-HT and dopamine. THA (100 microM)-evoked monoamine release was comparable, but not additive with the release produced by K+ (35 mM). The effect was not maximal at 1 mM THA. THA-evoked release of 5-HT was independent of the presence of Ca2+ in the external medium. 3 Drugs acting on the cholinergic system, nicotine, mecamylamine, atropine, oxotremorine, physostigmine and neostigmine (all 10 microM) had no effect on 5-HT and dopamine-release. 4-Aminopyridine (4-AP), a potent acetylcholine-releasing agent, had no effect on 5-HT release and was approximately 100 fold less active than THA on dopamine release. 4 Both THA and reserpine enhanced the release of 5-HT in the presence of the monoamine oxidase inhibitor, pargyline. Reserpine- but not THA-evoked release was abolished in the absence of pargyline. Reserpine (5 mg kg-1, i.p.) markedly depleted brain monoamine concentrations 3 h after injection, while THA (15 mg kg-1, i.p.) had no effect. 5 Chloroamphetamine and fenfluramine both released 5-HT in a Ca2(+)-independent manner and with a similar potency to THA, while (+)-amphetamine released dopamine with a similar potency to THA. The effects of the amphetamines were not maximal at 1 mM. However, unlike THA, chloroamphetamine-evoked release of 5-HT was additive with release evoked by K+ (35 mM). 6 Clomipramine (IC50 = 0.036 microM) and THA (IC50 = 19.9 microM) all inhibited the uptake of [3H]-5-HT into a P2 membrane preparation. However, none of these compounds inhibited [3H]-5-HT uptake into tissue prisms during the release experiments in which the reuptake inhibitor fluoxetine (5 microM) was present. 7 We conclude that THA does not release endogenous 5-HT through a cholinergic, reserpine- or amphetamine-like mechanism or through inhibition of reuptake. The possibility exists that the release may occur via blockade of 4-AP-insensitive K+ channels.

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Selected References

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  1. Arzate M. E., Morán J., Pasantes-Morales H. Inhibitory effect of taurine on 4-aminopyridine-stimulated release of labelled dopamine from striatal synaptosomes. Neuropharmacology. 1986 Jul;25(7):689–694. doi: 10.1016/0028-3908(86)90083-3. [DOI] [PubMed] [Google Scholar]
  2. Auerbach S., Lipton P. Regulation of serotonin release from the in vitro rat hippocampus: effects of alterations in levels of depolarization and in rates of serotonin metabolism. J Neurochem. 1985 Apr;44(4):1116–1130. doi: 10.1111/j.1471-4159.1985.tb08733.x. [DOI] [PubMed] [Google Scholar]
  3. Cross A. J., Crow T. J., Peters T. J. Cortical neurochemistry in Alzheimer-type dementia. Prog Brain Res. 1986;70:153–169. doi: 10.1016/s0079-6123(08)64303-4. [DOI] [PubMed] [Google Scholar]
  4. Dolezal V., Tucek S. The effects of 4-aminopyridine and tetrodotoxin on the release of acetylcholine from rat striatal slices. Naunyn Schmiedebergs Arch Pharmacol. 1983 Jun;323(2):90–95. doi: 10.1007/BF00634254. [DOI] [PubMed] [Google Scholar]
  5. Drukarch B., Kits K. S., Van der Meer E. G., Lodder J. C., Stoof J. C. 9-Amino-1,2,3,4-tetrahydroacridine (THA), an alleged drug for the treatment of Alzheimer's disease, inhibits acetylcholinesterase activity and slow outward K+ current. Eur J Pharmacol. 1987 Sep 2;141(1):153–157. doi: 10.1016/0014-2999(87)90424-9. [DOI] [PubMed] [Google Scholar]
  6. Drukarch B., Leysen J. E., Stoof J. C. Further analysis of the neuropharmacological profile of 9-amino-1,2,3,4-tetrahydroacridine (THA), an alleged drug for the treatment of Alzheimer's disease. Life Sci. 1988;42(9):1011–1017. doi: 10.1016/0024-3205(88)90431-6. [DOI] [PubMed] [Google Scholar]
  7. Giorguieff-Chesselet M. F., Kemel M. L., Wandscheer D., Glowinski J. Regulation of dopamine release by presynaptic nicotinic receptors in rat striatal slices: effect of nicotine in a low concentration. Life Sci. 1979 Oct 1;25(14):1257–1262. doi: 10.1016/0024-3205(79)90469-7. [DOI] [PubMed] [Google Scholar]
  8. Giorguieff M. F., Le Floc'h M. L., Glowinski J., Besson M. J. Involvement of cholinergic presynaptic receptors of nicotinic and muscarinic types in the control of the spontaneous release of dopamine from striatal dopaminergic terminals in the rat. J Pharmacol Exp Ther. 1977 Mar;200(3):535–544. [PubMed] [Google Scholar]
  9. Hsieh J. Y., Yang R. K., Davis K. L. High-performance liquid chromatographic determination of tetrahydroaminoacridine in human and rat tissues using a rapid Sep-Pak C18 extraction. J Chromatogr. 1983 May 13;274:388–392. doi: 10.1016/s0378-4347(00)84449-7. [DOI] [PubMed] [Google Scholar]
  10. Hunter A. J., Murray T. K., Jones J. A., Cross A. J., Green A. R. The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro. Br J Pharmacol. 1989 Sep;98(1):79–86. doi: 10.1111/j.1476-5381.1989.tb16865.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kuhn D. M., Wolf W. A., Youdim M. B. 5-Hydroxytryptamine release in vivo from a cytoplasmic pool: studies on the 5-HT behavioural syndrome in reserpinized rats. Br J Pharmacol. 1985 Jan;84(1):121–129. [PMC free article] [PubMed] [Google Scholar]
  12. Lehmann J., Langer S. Z. Muscarinic receptors on dopamine terminals in the cat caudate nucleus: neuromodulation of [3H]dopamine release in vitro by endogenous acetylcholine. Brain Res. 1982 Sep 23;248(1):61–69. doi: 10.1016/0006-8993(82)91147-7. [DOI] [PubMed] [Google Scholar]
  13. Llinás R., Walton K., Bohr V. Synaptic transmission in squid giant synapse after potassium conductance blockage with external 3- and 4-aminopyridine. Biophys J. 1976 Jan;16(1):83–86. doi: 10.1016/S0006-3495(76)85664-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Niddam R., Arbilla S., Scatton B., Dennis T., Langer S. Z. Amphetamine induced release of endogenous dopamine in vitro is not reduced following pretreatment with reserpine. Naunyn Schmiedebergs Arch Pharmacol. 1985 Apr;329(2):123–127. doi: 10.1007/BF00501200. [DOI] [PubMed] [Google Scholar]
  15. Nilsson L., Adem A., Hardy J., Winblad B., Nordberg A. Do tetrahydroaminoacridine (THA) and physostigmine restore acetylcholine release in Alzheimer brains via nicotinic receptors? J Neural Transm. 1987;70(3-4):357–368. doi: 10.1007/BF01253610. [DOI] [PubMed] [Google Scholar]
  16. Osterrieder W. 9-Amino-1,2,3,4-tetrahydroacridine (THA) is a potent blocker of cardiac potassium channels. Br J Pharmacol. 1987 Nov;92(3):521–525. doi: 10.1111/j.1476-5381.1987.tb11352.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Palmer A. M., Stratmann G. C., Procter A. W., Bowen D. M. Possible neurotransmitter basis of behavioral changes in Alzheimer's disease. Ann Neurol. 1988 Jun;23(6):616–620. doi: 10.1002/ana.410230616. [DOI] [PubMed] [Google Scholar]
  18. Parker E. M., Cubeddu L. X. Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding. J Pharmacol Exp Ther. 1988 Apr;245(1):199–210. [PubMed] [Google Scholar]
  19. Pearce B. D., Potter L. T. Effects of tetrahydroaminoacridine on M1 and M2 muscarine receptors. Neurosci Lett. 1988 Jun 7;88(3):281–285. doi: 10.1016/0304-3940(88)90224-8. [DOI] [PubMed] [Google Scholar]
  20. Perry E. K., Smith C. J., Court J. A., Bonham J. R., Rodway M., Atack J. R. Interaction of 9-amino-1,2,3,4-tetrahydroaminoacridine (THA) with human cortical nicotinic and muscarinic receptor binding in vitro. Neurosci Lett. 1988 Aug 31;91(2):211–216. doi: 10.1016/0304-3940(88)90770-7. [DOI] [PubMed] [Google Scholar]
  21. Rapier C., Lunt G. G., Wonnacott S. Stereoselective nicotine-induced release of dopamine from striatal synaptosomes: concentration dependence and repetitive stimulation. J Neurochem. 1988 Apr;50(4):1123–1130. doi: 10.1111/j.1471-4159.1988.tb10582.x. [DOI] [PubMed] [Google Scholar]
  22. Reiner P. B., McGeer E. G. THA increases action potential duration of central histamine neurons in vitro. Eur J Pharmacol. 1988 Oct 18;155(3):265–270. doi: 10.1016/0014-2999(88)90512-2. [DOI] [PubMed] [Google Scholar]
  23. Rogawski M. A. Tetrahydroaminoacridine blocks voltage-dependent ion channels in hippocampal neurons. Eur J Pharmacol. 1987 Oct 6;142(1):169–172. doi: 10.1016/0014-2999(87)90670-4. [DOI] [PubMed] [Google Scholar]
  24. SHAW F. H., BENTLEY G. A. The pharmacology of some new anti-cholinesterases. Aust J Exp Biol Med Sci. 1953 Dec;31(6):573–576. doi: 10.1038/icb.1953.62. [DOI] [PubMed] [Google Scholar]
  25. Sakurai Y., Takano Y., Kohjimoto Y., Honda K., Kamiya H. O. Enhancement of [3H]dopamine release and its [3H]metabolites in rat striatum by nicotinic drugs. Brain Res. 1982 Jun 17;242(1):99–106. doi: 10.1016/0006-8993(82)90499-1. [DOI] [PubMed] [Google Scholar]
  26. Schauf C. L., Sattin A. Tetrahydroaminoacridine blocks potassium channels and inhibits sodium inactivation in Myxicola. J Pharmacol Exp Ther. 1987 Nov;243(2):609–613. [PubMed] [Google Scholar]
  27. Steinberg G. M., Mednick M. L., Maddox J., Rice R. A hydrophobic binding site in acetylcholinesterase. J Med Chem. 1975 Nov;18(11):1057–1061. doi: 10.1021/jm00245a002. [DOI] [PubMed] [Google Scholar]
  28. Stevens D. R., Cotman C. W. Excitatory actions of tetrahydro-9-aminoacridine (THA) on hippocampal pyramidal neurons. Neurosci Lett. 1987 Aug 31;79(3):301–305. doi: 10.1016/0304-3940(87)90448-4. [DOI] [PubMed] [Google Scholar]
  29. Summers W. K., Majovski L. V., Marsh G. M., Tachiki K., Kling A. Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. N Engl J Med. 1986 Nov 13;315(20):1241–1245. doi: 10.1056/NEJM198611133152001. [DOI] [PubMed] [Google Scholar]
  30. Tapia R., Sitges M. Effect of 4-aminopyridine on transmitter release in synaptosomes. Brain Res. 1982 Nov 4;250(2):291–299. doi: 10.1016/0006-8993(82)90423-1. [DOI] [PubMed] [Google Scholar]
  31. Vizi E. S., van Dijk J., Foldes F. F. The effect of 4-aminopyridine on acetylcholine release. J Neural Transm. 1977;41(4):265–274. doi: 10.1007/BF01252021. [DOI] [PubMed] [Google Scholar]
  32. Westfall T. C., Grant H., Perry H. Release of dopamine and 5-hydroxytryptamine from rat striatal slices following activation of nicotinic cholinergic receptors. Gen Pharmacol. 1983;14(3):321–325. doi: 10.1016/0306-3623(83)90037-x. [DOI] [PubMed] [Google Scholar]
  33. Yeh J. Z., Oxford G. S., Wu C. H., Narahashi T. Interactions of aminopyridines with potassium channels of squid axon membranes. Biophys J. 1976 Jan;16(1):77–81. doi: 10.1016/S0006-3495(76)85663-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

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