Clonidine prevents transient loss of noradrenaline in response to cholinergic hypofunction induced by ethylcholine aziridinium (AF64A).
Intracerebroventricular injection of ethylcholine aziridinium (AF64A) (2 nmol/ventricle) induced a considerable decrease in the level of acetylcholine (ACh) in hippocampus (from 21.14 +/- 0.84 to 10.04 +/- 0.59 pmol/mg of tissue; p less than 0.001) 4 days after application. The reduction of cholinergic function was accompanied by a decrease in the level of noradrenaline (NA) (from 1.96 +/- 0.08 to 1.41 +/- 0.06 pmol/mg of tissue; p less than 0.001). Two days after administration of AF64A (1 or 2 nmol/ventricle), the dose-dependent decrease in NA level was associated with an increase in the level of its major metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), resulting in a considerable increase in the MHPG/NA molar ratio (from 0.84 +/- 0.06 to 1.62 +/- 0.17; p less than 0.002). Chronic treatment of AF64A-injected rats with clonidine (0.02-0.2 mg/kg, i.p., every 8-12 h) had no significant effect on the loss of ACh content, whereas the decrease in NA content in hippocampus was completely prevented. Clonidine induced aggressive behavior in the AF64A-treated rats, in contrast to sedation in vehicle-injected rats. The response to clonidine under these experimental conditions and the increased MHPG/NA molar ratio in response to AF64A suggest that the transient loss of NA content following AF64A administration results from increased NA release. The increased noradrenergic activity in hippocampus may be linked to the reduction of tonic inhibitory cholinergic input. These results are discussed in relation to possible implications for senile dementia of the Alzheimer type.
Hörtnagl
H
H
Department of Pharmacology and Experimental Therapeutics, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL 60153.
Potter
P E
PE
Singer
E A
EA
Kindel
G
G
Hanin
I
I
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001388:Aziridines / Q000008:administration & dosage / Q000494:pharmacology*; D001389:Azirines / Q000494:pharmacology*; D002794:Choline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007276:Injections, Intraventricular; D007700:Kinetics; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000378:metabolism; D009466:Neuromuscular Blocking Agents; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D001388:Aziridines; D001389:Azirines; D009466:Neuromuscular Blocking Agents; D008734:Methoxyhydroxyphenylglycol; C044894:ethylcholine aziridinium; D002795:Choline O-Acetyltransferase; D003000:Clonidine; D002794:Choline; D000109:Acetylcholine; D009638:Norepinephrine