MUSCARINIC, N-METHYL-D-ASPARTATE (NMDA) AND BENZODIAZEPINE RECEPTOR-BINDING SITES IN CORTICAL MEMBRANES FROM AMYOTROPHIC-LATERAL-SCLEROSIS PATIENTS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder causing marked pathology in the motoneuron system. The patho physiology of the selective degeneration of motor neurons in the disea se is as yet unknown, but evidence suggests that excitotoxic mechanism s might be involved. The present study was undertaken to determine whe ther defects in neurotransmitter receptors are involved in the disease , analyzing uniformly sampled specimens from neocortex and motorcortex , The binding to benzodiazepine, muscarinic cholinergic, and NMDA rece ptors in ALS brains was compared to that in control brains, using a si ngle radioligand concentration of [H-3]Ro 15-1788, [H-3]QNB and [H-3]M K-801. The benzodiazepine and the muscarinic cholinergic receptor bind ing was unaffected in any cortical region from the ALS subjects compar ed to controls. NMDA receptor binding labeled by [H-3]MK-801 was signi ficantly increased in several neocortical regions in the ALS group com pared to the control group. Scatchard analysis of [H-3]MK-801 binding in frontal cortex revealed a single binding site with an unaltered max imal binding capacity but an increased binding affinity of the site in the ALS group compared to the controls. The generalized alteration in the affinity of the binding site for [H-3]MK-801 in the ALS cortex ma y indicate a modification of the NMDA receptor due to different sensit ivity for endogenous modulators or to a different subunit composition of the NMDA receptor in ALS with altered functional properties. These findings may reflect a pathophysiological phenomenon in ALS.