RT Journal Article
SR Electronic
T1 Long-term central cholinergic hypofunction induced in mice by ethylcholine aziridinium ion (AF64A) in vivo.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 140
OP 145
VO 222
IS 1
A1 A Fisher
A1 C R Mantione
A1 D J Abraham
A1 I Hanin
YR 1982
UL http://jpet.aspetjournals.org/content/222/1/140.abstract
AB Ethylcholine mustard aziridinium ion (AF64A), a neurotoxic choline analog, was evaluated for its interactions with the cholinergic system in mice. Parenterally administered AF64A was lethal (LD50 = 32.6 mumol/kg i.v.) and the lethality could be antagonized even at 8 LD50 doses by pretreatment with choline (714 mumol/kg i.p.) 2 min earlier. Mice that were protected by choline slowly developed neurological motor disturbances such as ataxia and hypokinesia, and lost weight. Intracerebroventricular administration of 65 nmol of AF64A was not acutely lethal, but produced similar delayed behavioral effects similar to those found after parenteral administration of AF64A. Seven days after a single injection of 65 nmol of AF64A i.c.v., there was a significant decrease in acetylcholine content in the cortex, striatum and hippocampus, but no change in choline levels. Acetylcholine content was still significantly reduced in the hippocampus at 3 weeks after this treatment. The reduction in activity of choline acetyltransferase and high-affinity choline transport paralleled the reduction in acetylcholine measured at 7 days post AF64A treatment, whereas muscarinic receptors in all three brain areas were unchanged. These combined data indicate that AF64A is a presynaptic chemical neurotoxin, capable of inducing a persistent deficiency in central cholinergic transmission.