Global in vivo replacement of choline by N-aminodeanol. Testing a hypothesis about progressive degenerative dementia: I. Dynamics of choline replacement.
Severe disruption of certain cholinergic pathways is a characteristic feature of Alzheimer's disease. Attempts to establish animal models by interfering with cholinergic function have not been very successful. We now present data which show a substantial and progressive replacement of free and phospholipid-bound choline by the novel choline isostere N-amino-N,N-dimethylaminoethanol during its dietary administration in place of choline. Free choline in blood fell to approximately 20% of controls after 10 to 30 days on diet. Phospholipid-bound choline in plasma was reduced to less than 15%, and in erythrocytes to about 22%. After 120 days of diet free and bound choline were reduced in most tissues to approximately 30% of controls. Only liver retained more than 80% of free choline. Acetylcholine was decreased to 33 to 50% of control. Total true and false transmitter in experimental animals was in all tissues less that acetylcholine in controls, suggesting that muscarinic transmission would be impaired. Moderate reduction of choline acetyltransferase activity was seen in striatum and myenteric plexus, and of QNB-binding in hippocampus, striatum and myenteric plexus.
Knusel
B
B
Department of Pharmacology, School of Medicine, University of California, Los Angeles 90024.
Jenden
D J
DJ
Lauretz
S D
SD
Booth
R A
RA
Rice
K M
KM
Roch
M
M
Waite
J J
JJ
D000107:Acetylation; D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000378:metabolism; D002794:Choline / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004032:Diet; D005260:Female; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D011247:Pregnancy; D011813:Quinuclidinyl Benzilate / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects
D018377:Neurotransmitter Agents; D010743:Phospholipids; D011976:Receptors, Muscarinic; C038146:N-amino-N,N-dimethylaminoethanol; D011813:Quinuclidinyl Benzilate; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002794:Choline