title: Induction of cortical cholinergic hypofunction and memory retention deficits through intracortical AF64A infusions.
abstract: Ethylcholine mustard aziridinium ion (AF64A), an irreversible inhibitor of high-affinity choline uptake on cholinergic nerve terminals, appears to selectively decrease presynaptic cholinergic markers after intracerebral injection. To restrict AF64A's action to cholinergic terminals within the frontoparietal (FP) cortex, the present study utilized multiple-site cortical infusions of the agent. Following an extensive histological analysis, a dose of 1 nmol AF64A/1 microliter was selected for determining AF64A's effects on acetylcholinesterase (AChE) staining, cortical cholinergic/non-cholinergic markers, and passive avoidance behavior. Adult rats given two infusions of AF64A into the right FP cortex had reduced AChE staining throughout 75% of the ipsilateral FP cortex at 10 days following infusion, thus suggesting an extensive cortical diffusion of the agent; minimal non-specific damage was seen (totalling only 4% of the ipsilateral FP cortex for both infusion sites) and no effects on AChE staining were observed in the striatum or hippocampus. Three weeks after bilateral AF64A infusions into the FP cortex (two injections on each side), significant frontal cortex deficits were observed in high-affinity choline uptake, acetylcholine synthesis, acetylcholine release, and hemicholinium-3 binding compared to vehicle-infused controls. However, choline acetyltransferase activity within the anterior cortex did not appear to be consistently affected by AF64A infusion. Cortical glutamic acid decarboxylase activity, as well as cortical monoaminergic markers, and neuropeptide levels were also unaffected. Moreover, animals that received bilateral AF64A infusions and were tested two weeks afterwards showed marked memory retention deficits during both the 24-h and 48-h postshock trials of passive avoidance testing. These results indicate that cortical AF64A infusion induces a specific, long-term cholinergic hypofunction of presynaptic markers within the cortex, resulting in a significant long-term memory impairment. Since the primary cholinergic innervation to the FP cortex, originating in the nucleus basalis of Meynert, appears to become dysfunctional (but not totally degenerative) in Alzheimer's disease, cortical AF64A infusions may closely reflect this cholinergic dysfunction by 'functionally' eliminating cortical cholinergic terminals.
authors: Department of Biology, University of South Florida, Tampa 33620.
authors: P R
authors: PR
authors: Mouton
authors: E M
authors: EM
authors: Meyer
authors: A J
authors: AJ
authors: Dunn
authors: W
authors: W
authors: Millard
authors: G W
authors: GW
authors: Arendash
mesh_terms: D000109:Acetylcholine / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001388:Aziridines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001389:Azirines / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D002794:Choline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D007263:Infusions, Parenteral; D008297:Male; D008568:Memory / Q000187:drug effects*; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D001388:Aziridines; D001389:Azirines; D009466:Neuromuscular Blocking Agents; C044894:ethylcholine aziridinium; D002795:Choline O-Acetyltransferase; D002794:Choline; D000109:Acetylcholine