Autoradiographic Localization Studies Of The Distribution Of M2 Receptors Suggest A Presynaptic Location On Cholinergic Tracts: Implications For Alzheimer's Disease (muscarinic, Autoreceptor)

In vitro autoradiographic studies of muscarine receptors demonstrated that M1 and M2 receptors were differentially located in specific areas of the brain. Two new methods were employed in these studies which revealed the distribution of M2 receptors for the first time. M1 receptors predominated in the forebrain. M2 receptors were distributed throughout the brain and were dense over regions known to be rich in cholinergic cell bodies. In the hippocampus there was a correspondence between acetylcholinesterase-positive sites and M2 receptors. These observations, taken together with evidence that M2 receptors undergo axonal transport, suggested that M2 receptors were a neurochemical marker for cholinergic tracts.Excitotoxic lesions of extrinsic cholinergic inputs to the frontoparietal cortex in the rat, resulted in a 60 to 90% reduction in choline acetyltransferase activity and an almost complete loss of the radial acetylcholinesterase-stained axons in the frontoparietal cortex. Carbachol competition with ('3)H-quinuclidinyl benzilate demonstrated that 42% of the total receptors in the frontoparietal cortex of the rat were M2. An ibotenic acid lesion of peripallidal neurons resulted in a 50-90% reduction of M2 receptors.The status of M1 and M2 receptors was assessed in the frontal and infratemporal cortex from ten Alzheimer-diseased brains. Carbachol competition studies or direct measures with ('3)H-oxotremorine-M revealed significant reductions in M2 receptors. M2 receptor decreases were concomitant with reductions in choline acetyltransferase activity.These results suggest that M2 receptors function in cholinergic terminals as autoreceptors. In addition, they provide a rationale for using an M-2 selective antagonist together with esterase inhibition to augment acetylcholine release in Alzheimer's disease.