INTERACTIONS OF NEUROTOXINS WITH NON-NMDA GLUTAMATE RECEPTORS - AN AUTORADIOGRAPHIC STUDY

Neurotoxic substances are discussed to cause neurodegeneration by acti ng as excitotoxins on glutamate receptors. We investigated the propert ies of L-beta-oxalyl-amino-alanine (L-BOAA) and 3,4,6-trihydroxyphenyl alanine (6-OH-Dopa) at the pha-amino-3-hydroxy-5-methyl-4-isoxazole-pr opionic acid (AMPA) glutamate receptor and that of L-BOAA and domoic a cid at the kainate glutamate receptor in human hippocampus. (H-3)AMPA binding in hippocampal subfields was inhibited by L-BOAA and 6-OH-Dopa with mean IC50-values in the low micromolar range. (3H)Kainate bindin g was inhibited by L-BOAA with similar potency as (3H)AMPA binding and by domoic acid with mean IC50-values in the low nanomolar range. Thes e results support the notion that symptoms like anterograde amnesia an d epileptic seizures seen in domoic acid intoxication and limbic sympt oms, e.g. cognitive and mood impairment observed in neurolathyrism may be caused by excitotoxic action on non-NMDA receptors. The potent int eraction of 6-OH-Dopa with the AMPA-receptor may point to a possible d opaminergic-glutamatergic interaction in the development of neurodegen erative diseases like Parkinson's and Huntington's disease.