Specific toxic effects of ethylcholine nitrogen mustard on cholinergic neurons of the nucleus basalis of Meynert.
The putative cholinergic neurotoxin, ethylcholine aziridinium ion (AF64A), was injected unilaterally into the nucleus basalis of Meynert (nbM) in order to determine whether it would produce specific damage to the cholinergic cell bodies of this nucleus. Injections of small amounts of AF64A (0.01 nmol in 1 microliter) or of its vehicle had little effect on the appearance of the nbM or on the levels of choline acetyltransferase (ChAT) in the cortex. Injections of larger amounts of AF64A (0.02 and 0.05 nmol in 1 microliter and 0.02 nmol in 10 microliters) produced a loss of diffuse acetylcholinesterase staining in the nbM and a loss of large positively staining neurons. Furthermore, these injections produced a significant reduction of ChAT activity in the central portion of the cortex. However, non-cholinergic neurons in the area of the nbM were not affected by these AF64A injections. In addition, cortical uptake of monoamines was not affected by these lesions. Further increases in the amount of AF64A injected (0.1 nmol in 1 microliter and 0.035 nmol in 10 microliters) caused damage at the site of the injection which was not limited to the cholinergic elements of the nbM. These results suggest that AF64A can be used to produce specific lesions of cholinergic neurons, and therefore may be useful in developing animal models of human disorders involving cholinergic hypofunction, such as senile dementia of the Alzheimer type. However, there is a narrow dose range for producing these specific effects.
Kozlowski
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Arbogast
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D000818:Animals; D001388:Aziridines / Q000008:administration & dosage / Q000633:toxicity*; D001389:Azirines / Q000633:toxicity*; D001479:Basal Ganglia / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D001931:Brain Mapping; D002395:Catecholamines / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002794:Choline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009466:Neuromuscular Blocking Agents / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013377:Substantia Innominata / Q000187:drug effects* / Q000473:pathology
D001388:Aziridines; D001389:Azirines; D002395:Catecholamines; D009466:Neuromuscular Blocking Agents; C044894:ethylcholine aziridinium; D002795:Choline O-Acetyltransferase; D002794:Choline