Changes of cholinergic, noradrenergic and serotonergic synaptic transmission indices elicited by ethylcholine aziridinium ion (AF64A) infused intraventricularly.
Bilateral (3 nmol/side) i.c.v. infusion of ethylcholine aziridinium ion (AF64A) causes a 70% decrease of hippocampal acetylcholine content lasting for longer than 30 days without changing the density of hippocampal recognition sites for muscarinic ligands. In hippocampal slices prepared from rats receiving i.c.v. AF64A, the activation of phosphoinositide turnover or the inhibition of cyclic AMP accumulation elicited by muscarinic receptor agonists is facilitated. This AF64A treatment also causes a long-lasting decrease of hippocampal norepinephrine and serotonin (5-HT) content. Even a smaller dose of AF64A (1.5 nmol/side) reduces the hippocampal 5-HT content. The number of alpha-1 adrenoceptor recognition sites is slightly increased by 3 nmol/side of AF64A and the stimulation of phosphoinositide turnover by norepinephrine is facilitated. In contrast the decrease of hippocampal 5-HT concentration elicited by AF64A fails to change the 5-HT receptor indices that were measured. These results indicate that in rat hippocampus muscarinic receptors and alpha-1 adrenoceptors are denervated by AF64A and that this denervation promotes a receptor supersensitivity. These results also suggest that we could not find appropriate conditions to express a complete specificity of AF64A in destroying cholinergic axons and therefore this drug cannot be used readily to induce a selective deficiency of central cholinergic transmission.
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001388:Aziridines / Q000008:administration & dosage / Q000494:pharmacology*; D001389:Azirines / Q000494:pharmacology*; D001665:Binding Sites; D002794:Choline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007276:Injections, Intraventricular; D009638:Norepinephrine / Q000378:metabolism*; D011224:Prazosin / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*
D001388:Aziridines; D001389:Azirines; D005576:Colforsin; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C044894:ethylcholine aziridinium; D000242:Cyclic AMP; D002794:Choline; D000109:Acetylcholine; D009638:Norepinephrine; D011224:Prazosin