LONG-TERM CENTRAL CHOLINERGIC HYPOFUNCTION INDUCED IN MICE BY ETHYLCHOLINE AZIRIDINIUM ION (AF64A) INVIVO

  • 1 January 1982
    • journal article
    • research article
    • Vol. 222  (1) , 140-145
Abstract
Recent research has indicated that central cholinergic hypofunction may be involved primarily in the pathology of senile dementia of Alzheimer''s type, and secondarily in other neurological and psychiatric disorders, e.g., tardive dyskinesia, Huntington''s disease, Friedreich''s ataxia and Gilles de la Tourette''s disease. An adequate animal model for one or more of these diseases would be one in which the synthesis of ACh is permanently impaired in vivo. So far, there are no known pharmacological agents capable of inducing such a sustained decrease in central cholinergic function. 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 .mu.mol/kg i.v.), and the lethality could be antagonized even at 8 LD50 doses by pretreatment with choline (714 .mu.mol/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 [i.c.v.] administration of 65 nmol 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 wk 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 3 brain areas were unchanged. AF64A is evidently a presynaptic chemical neurotoxin, capacity of inducing a persistent deficiency in central cholinergic transmission.