CHARACTERIZATION OF MUSCARINIC RECEPTOR SUBTYPES IN ALZHEIMER AND CONTROL BRAIN CORTICES BY SELECTIVE MUSCARINIC ANTAGONISTS

Subtypes of muscarinic receptors were characterized in the frontal cortices of control and Alzheimer brains, with labelled quinuclidinyl benzilate [H-3]QNB and the unlabelled muscarinic antagonists pirenzepine, AF-DX 116, hexahydro-sila-diphenidol (HHSiD), para-fluoro-hexahydro-sila-diphenidol (p-F-HHSiD) and himbacine. High and low affinity sites were observed for both pirenzepine and AF-DX 116 in human control frontal cortices. The majority (76%) of the pirenzepine binding sites showed high affinity to the muscarinic receptors (M1), while the rest of the binding sites had an affinity that was 40 times less. AF-DX 116 displayed two sets of binding sites where the high affinity AF-DX 116 (M2) sites constituted 27%, while the low affinity AF-DX 116 (non-M2 Site) was 73%. A single class of binding sites was observed for HHSiD, p-F-HHSiD and himbacine in human frontal cortices. HHSiD showed an affinity in the frontal cortices that was comparable to that of the pirenzepine high affinity binding (M1) sites. The affinity of p-F-HHSiD was three times lower than that of HHSiD but similar to himbacine. A significant increase in the affinity (+40%) as well as in the B(+99%) value was observed for the pirenzepine high affinity binding sites (M1) in the frontal cortices of Alzheimer brains compared to controls. Similarly, a significant increase was observed in the B(max) value (+60%) for the AF-DX 116 low affinity binding sites (non-M2), while no change was found for the high affinity binding sites (M2). HHSiD showed an increase in both B(max) (+54%) and affinity (+20%) while the binding properties of p-F-HHSiD and himbacine were unchanged in Alzheimer brains compared to controls. The results indicate a preservation of the muscarinic receptors in Alzheimer frontal cortices with a relative increase in the number of M1 receptor sites.