Acetylcholine Receptor Targets on Cortical Pyramidal Neurones as Targets for Alzheimer's Therapy

Experimental lesions using the retrogradely transported toxin, volkensin, have been used in conjunction with autoradiography to investigate the cellular localization of 5–HT_1A, muscarinic M₁and nicotinic receptors. Selective destruction of neocortical pyramidal neurones forming the corticostriatal or corticocortical pathways was achieved by intrastriatal or intracortical injection of volkensin. Selective destruction of layer V corticostriatal neurones was accompanied by loss of binding in the cortex to 5–HT_1Aand muscarinic M₁receptors, and an upregulation of [³H] nicotine binding contralateral to the pyramidal cell loss. Destruction of corticocortical neurones was accompanied by loss of binding to muscarinic and nicotinic receptors. The presence of these cholinoceptors on corticocortical neurones was confirmed by recording carbachol-induced depolarizations from a novel cortical brain slice preparation. It is proposed that cholinoceptors represent a consistent marker for neocortical pyramidal cells, and as such are viable targets for the continuing development of therapies designed to ameliorate the cortical hypoactivity observed in Alzheimer's disease. Ligands for these receptors may also be suitable for positron emission tomography to assess pyramidal neurone numbers in suspected Alzheimer's disease.