Abstract
Acetylcholine (ACh) levels were determined in rat midbrain and caudate nucleus and mouse whole brain in mature animals adapted 3 weeks to a programmed lighting schedule (08:00 to 20:00 h light; 20:00 to 08:00 dark). Peak ACh levels in the rat occurred at 24:00 h; in the mouse the peak at 06:00 h did not differ significantly from values obtained at 24:00 and 12:00 h. Significant trough values occurred at 12:00 h in rat midbrain and at 18:00h in rat caudate nucleus and mouse brain. In mice toxicity of I.V. and I.P. administered ACh is maximal during the dark. Neostigmine, pilocarpine and oxotremorine have toxicity patterns similar to ACh. Carbachol toxicity peaked at 12:00 and 24:00 h. With physostigmine, a tertiary anticholinesterase, peak and trough occurred during the dark. The atropine (I.P.) toxicity rhythm is a mirror image of the cholinomimetic rhythm (except for carbachol). I.V. scopolamine and atropine methyl nitrate patterns resemble atropine's but are less clear-cut. Atropine methyl nitrate pretreatment reduced ACh and physostigmine toxicity but did not alter the overall pattern. Cholinomimetic toxicity and brain ACh patterns are similar, peaking when metabolic activity is maximal. An inverse relationship holds for the anticholinergic drugs. The relationship to central ACh is uncertain.
Zusammenfassung
Nach Adaptation an ein Licht-Dunkelprogramm (8.00 bis 20.00 Licht, 20.00 bis 8.00 Dunkelheit) wurde der Acetylcholingehalt (ACh) im Mittelhirn und N. caudatus von Ratten sowie im Gesamthirn von Mäusen bestimmt. Die höchsten ACh-Konzentrationen wurden bei Ratten um 24.00 gefunden; die höchsten ACh-Werte bei der Maus waren nicht signifikant von den Konzentrationen um 24.00 und 12.00 verschieden. Signifikante ACh-Minima traten im Mittelhirn der Ratte um 12.00, im N. caudatus sowie im Mäusegehirn um 18.00 Uhr auf.
Während der Dunkelperiode wurde die größte Toxicität gegenüber i.v. bzw. i.p. injiziertem ACh bei Mäusen gefunden. Ähnliche zeitliche Unterschiede ergaben sich für Neostigmin, Pilocarpin und Oxytremorin. Die Toxicität von Carbachol zeigte Maxima bei 12.00 und 24.00. Für Physostigmin, einen CholinesteraseHemmstoff mit einem tertiären Stickstoff, lagen sowohl die Toxicitätsmaxima als auch die Toxicitätsminima in der Dunkelperiode.
Die rhythmische Schwankung der Toxicität von i.p. verabfolgtem Atropin verhielt sich umgekehrt wie die der Cholinomimetica (außer Carbachol). Auch nach i.v. Applikation von Scopolamin und N-Methylatropin war ein entsprechender rhythmischer Einfluß auf die Toxicität nachweisbar. Die Vorbehandlung mit N-Methylatropin schwächte die Toxicität zwar ab, der Toxicitätsrhythmus gegenüber ACh und Physostigmin war aber nicht verändert.
Die Toxicität von Cholinomimetica zeigt ein Maximum während der höchsten ACh-Konzentrationen im Gehirn und der höchsten Stoffwechselaktivität. Bei den anticholinergen Substanzen zeigte sich ein umgekehrtes Verhältnis. Die Beziehungen zum zentralen ACh-Gehalt sind unklar.
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Rat brain acetylcholine data and some of the toxicity curves contained in this paper were presented by the authors in a talk at the Symposium on Circadian Rhythms in Pharmacology and Biochemistry organized by Dr. Julius Axelrod at the Spring Meeting of the Federation of American Societies for Experimental Biology, Atlantic City, New Jersey, 1969, under the title: Circadian Rhythms in Central Acetylcholine and the Toxicity of Cholinergic Drugs.
Confirmation of our findings of rat brain ACh rhythms have subsequently been made by Hanin, Massarelli, and Costa, Science 170, 341 (1970) and by E. Domino et al., (submitted for publication). Saito, Life Sciences 10, (1) 735 (1971) recently reported circadian rhythms for free and bound ACh in rat brain.
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Friedman, A.H., Walker, C.A. The acute toxicity of drugs acting at cholinoceptive sites and twenty-four hour rhythms in brain acetylcholine. Arch Toxicol 29, 39–49 (1972). https://doi.org/10.1007/BF00316513
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DOI: https://doi.org/10.1007/BF00316513
Key words
- Mouse
- Rat
- Brain
- Light-Dark-Programming
- Circadian
- Toxicity Rhythms
- Acetylcholine
- Pilocarpine
- Oxotremorine
- Carbachol
- Physostigmine
- Neostigmine
- Atropine
- Scopolamine
- Atropine Methyl Nitrate