Behavioral and neuroanatomical consequences of a unilateral intraventricular infusion of AF64A and limitations on the neuroprotective effects of nimodipine.
The monoethylcholine aziridinium ion, AF64A, (3 nmol in 1 microliter) or artificial CSF (1 microliter) was infused unilaterally into the right dorsal lateral ventricle of male adult rats. Treatment with the L-type calcium channel antagonist, nimodipine (70 micrograms/kg b.wt.) or its vehicle was administered beginning before and for seven days following surgery. The infusion of AF64A reduced spontaneous alternation rates in the T-maze when compared to CSF and sham infused animals. AF64A-treated animals also took longer to reach the goal area in a complex maze task on specific trials relative to CSF and sham-infused animals. Locomotion and habituation to the open field did not differ between surgery groups. Unilateral AF64A significantly depleted acetylcholinesterase (AChE) positive terminals in the ipsilateral hippocampus and cell bodies in the ipsilateral medial septal area (MSA). Receptors for nerve growth factor (NGF-R), often colocalized with cholinergic cell bodies and terminals, also were depleted in the ipsilateral MSA of AF64A infused animals. Treatment with nimodipine did not have a neuroprotective effect on AF64A animals in either behavioral or histological results. However, some degree of protection was found in the vehicle-treated rats. This effect was likely a consequence of the stress of the injection procedure rather than the content of the vehicle, largely polyethylene glycol 400. Nimodipine-treated animals, regardless of surgery group, exhibited fewer emotional responses and had lower spontaneous alternation rates than untreated animals. The behavioral alterations found in the nimodipine groups are most easily explained in terms of altered emotionality. Overall our findings indicate that AF64A is a potent cholinotoxin that can selectively eliminate the ipsilateral septohippocampal cholinergic system when unilaterally infused into the lateral ventricle. It is possible that the mechanism of action of AF64A, like other nitrogen mustard analogues, involves disruption of basic processes involved in protein synthesis and DNA activities. Because of this, the toxic effects of the aziridinium mustard are independent of extracellular calcium and thus may not be susceptible to protection by calcium channel antagonists.
Maier
D L
DL
Department of Anatomy and Cell Biology, State University of New York, Syracuse 13210.
Isaacson
R L
RL
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001388:Aziridines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000033:anatomy & histology* / Q000187:drug effects; D002794:Choline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004644:Emotions / Q000187:drug effects; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects; D006651:Histocytochemistry; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009434:Neural Pathways / Q000033:anatomy & histology / Q000187:drug effects; D009466:Neuromuscular Blocking Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009553:Nimodipine / Q000494:pharmacology*; D010275:Parasympathetic Nervous System / Q000033:anatomy & histology / Q000187:drug effects; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology
D001388:Aziridines; D009466:Neuromuscular Blocking Agents; D017475:Receptors, Nerve Growth Factor; D009553:Nimodipine; C044894:ethylcholine aziridinium; D000110:Acetylcholinesterase; D002794:Choline