Autoradiographic comparison of [3H](-)nicotine, [3H]cytisine and [3H]epibatidine binding in relation to vesicular acetylcholine transport sites in the temporal cortex in Alzheimer's disease.
The laminar binding distribution of three nicotinic receptor agonists, [3H](-)nicotine, [3H]cytisine, and [3H]epibatidine, and their relation to the [3H]vesamicol binding, which is known to represent the vesicular acetylcholine transport sites, was performed employing in vitro autoradiography on the medial temporal cortex (Brodmann area 21). Autopsied brain tissue from nine Alzheimer patients and seven age-matched controls were used. The binding pattern of the three nicotinic ligands in the normal cortex was in general similar, showing binding maxima in the cortical layers I, III and V. The binding of [3H](-)nicotine, [3H]cytisine, and [3H]epibatidine was lower in the older controls and more uniform throughout the layers as compared with younger controls. There was a significant age-related decrease in the binding of the three nicotinic ligands within the controls (age range: 58 to 89 years; P[3H](-)nicotine = 0.002, P[3H]epibatidine = 0.010, P[3H]cytisine = 0.037). In the older controls, the [3H]epibatidine binding was much decreased as compared with that of [3H](-)nicotine and [3H]cytisine. This may indicate a higher selectivity of [3H]epibatidine for a nicotinic receptor subtype that is particularly affected by aging. The laminar binding pattern of [3H]vesamicol showed one maximum in the outer cortical layers II/III. The [3H]vesamicol binding did not change with aging. The binding of all ligands was significantly decreased in all layers of the temporal cortex in Alzheimer's disease, but the [3H]vesamicol binding decreased only half as much as the nicotinic receptors. Also, choline acetyltransferase activity was percentually more reduced than [3H]vesamicol binding in Alzheimer's disease. The cortical laminar binding pattern of all 3H-ligands was largely absent in the Alzheimer's disease cases. The less severe loss of vesicular acetylcholine transport sites as compared with the loss of the nicotinic receptors and choline acetyltransferase activity may suggest that vesamicol binding sites might be more preserved in presynaptic terminals still existing and thereby expressing compensatory capacity to maintain cholinergic activity.
Sihver
W
W
PET Center Uppsala, Uppsala University, Sweden. wiebke.sihver@pet.uu.se
Gillberg
P G
PG
Svensson
A L
AL
Nordberg
A
A
D000109:Acetylcholine / Q000378:metabolism; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000470:Alkaloids / Q000493:pharmacokinetics*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001345:Autoradiography / Q000379:methods; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics*; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009538:Nicotine / Q000493:pharmacokinetics*; D010880:Piperidines / Q000493:pharmacokinetics; D011725:Pyridines / Q000493:pharmacokinetics*; D011807:Quinolizines; D012016:Reference Values; D013702:Temporal Lobe / Q000378:metabolism* / Q000473:pathology; D014316:Tritium; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D000093843:Quinolizidine Alkaloids
D000109:Acetylcholine; D000470:Alkaloids; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D009538:Nicotine; D010880:Piperidines; D011725:Pyridines; D011807:Quinolizines; D014316:Tritium; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; C493459:SLC18A3 protein, human; C006189:vesamicol; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C082748:epibatidine