Regional differences in ethylcholine mustard aziridinium ion (AF64A)-induced deficits in presynaptic cholinergic markers for the rat central nervous system.
Several highly selective biochemical markers were used to assess the persistent central cholinergic dysfunction which accompanies administration of the cholinergic neurotoxin ethylcholine mustard aziridinium ion (AF64A). Rats received a single bilateral intracerebroventricular injection of AF64A (3 nmol/3 microliter/side) or vehicle and measurements were carried out in the cerebral cortices, hippocampi and corpora striata at 7 and 21 days postinjection. The drug binding sites of muscarinic cholinergic receptors, as revealed by high-affinity binding of (-)-[3H]quinuclidinyl benzilate (a classical muscarinic antagonist), [3H]pirenzepine (a selective antagonist of the putative M1 muscarinic receptor subclass) and (+)-[3H]cis-methyldioxolane (a potent muscarinic agonist), were not significantly affected by AF64A treatment. As reported previously, activity of the cholinergic synthetic enzyme choline acetyltransferase was reduced markedly (60-65%) in the hippocampi of AF64A-treated rats. A similar reduction was noted in high-affinity binding of [3H]hemicholinium-3 (a putative radioligand for sodium-dependent high-affinity choline uptake sites on cholinergic nerve terminals) in hippocampal membranes (59-65%). However, in the cerebral cortex, these presynaptic cholinergic markers were differentially altered by AF64A pretreatment (choline acetyltransferase, unchanged; [3H]hemicholinium-3 binding, reduced by 59-65%). These results indicate that a single intracerebroventricular injection of AF64A promotes biochemical and possibly functional deficits in presynaptic cholinergic nerve terminals distal from the injection site while having minimal influences upon muscarinic cholinergic receptor populations.
D000818:Animals; D001388:Aziridines / Q000633:toxicity*; D001389:Azirines / Q000633:toxicity*; D001921:Brain / Q000187:drug effects*; D002794:Choline / Q000031:analogs & derivatives* / Q000633:toxicity; D002795:Choline O-Acetyltransferase / Q000032:analysis; D006426:Hemicholinium 3 / Q000378:metabolism; D008297:Male; D009466:Neuromuscular Blocking Agents / Q000633:toxicity*; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects; D014316:Tritium
D001388:Aziridines; D001389:Azirines; D009466:Neuromuscular Blocking Agents; D011976:Receptors, Muscarinic; D014316:Tritium; D006426:Hemicholinium 3; C044894:ethylcholine aziridinium; D002795:Choline O-Acetyltransferase; D002794:Choline