ACETYLCHOLINE-RECEPTOR TARGETS ON CORTICAL PYRAMIDAL NEURONS AS TARGETS FOR ALZHEIMERS THERAPY

Experimental lesions using the retrogradely transported toxin, volkens in, have been used in conjunction with autoradiography to investigate the cellular localization of 5-HT1(1A) muscarinic M(1) and nicotinic r eceptors. Selective destruction of neocortical pyramidal neurones form ing the corticostriatal or corticocortical pathways was achieved by in trastriatal or intracortical injection of volkensin. Selective destruc tion of layer V corticostriatal neurones was accompanied by loss of bi nding in the cortex to 5-HT1A and muscarinic M(1) receptors, and an up regulation of [H-3] nicotine binding contralateral to the pyramidal ce ll loss. Destruction of corticocortical neurones was accompanied by lo ss of binding to muscarinic and nicotinic receptors. The presence of t hese cholinoceptors on corticocortical neurones was confirmed by recor ding carbachol-induced depolarizations from a novel cortical brain sli ce preparation. It is proposed that cholinoceptors represent a consist ent marker for neocortical pyramidal cells, and as such are viable tar gets for the continuing development of therapies designed to ameliorat e the cortical hypoactivity observed in Alzheimer's disease. Ligands f or these receptors may also be suitable for positron emission tomograp hy to assess pyramidal neurone numbers in suspected Alzheimer's diseas e. (C) 1996 Academic Press limited