Muscarinic cholinergic receptor subtypes in normal human brain and Alzheimer's presenile dementia.

Brain muscarinic M1 and M2 binding sites, as defined by their affinity for pirenzepine, were studied in 24 regions of 3 normal control brains. For each region, the binding of [3H]QNB, a non-subtype selective antagonist, was saturable with a mean KD of 0.117 +/- 0.066 nM. Computer-assisted analysis of the pirenzepine competition binding curves yielded the amount of high affinity (M1) and low affinity sites (M2) as well as their respective Ki values for this ligand. The neocortex contained a mixed population of 67% M1 and 33% M2 sites, without locoregional heterogeneity. The muscarinic receptors of the caudate nucleus, putamen, pallidum, hippocampus and nucleus amygdalis were predominantly of the M1 type as well. The cerebellum and the brain-stem are examples of regions containing over 90% M2 sites. White matter structures like the centrum ovale appeared to contain low concentrations of [3H]QNB binding sites, predominantly of the M1 subtype. The data for the frontal cortex were compared with data obtained in 3 patients who died from Alzheimer's disease with very early onset: the muscarinic receptor concentrations were somewhat lower but their M1/M2 ratio remained unchanged. GTP caused an appreciable rightward shift and steepening of the carbachol competition binding curve in M2 predominant regions such as the pons, whereas only a slight shift was observed in the cortex. In the presence of GTP, the alkylating reagent N-ethylmaleimide caused a 35-fold increase of the affinity for carbachol in M2 predominant regions. In contrast, regions where the receptors are predominantly of the M1 type, N-ethylmaleimide caused only a 5-fold increase in agonist affinity. These findings confirm our previously formulated hypothesis that the ability of N-ethylmaleimide to modulate the agonist affinity is an additional criterion for the characterization of M1 and M2-type receptors.