2,4,5-trihydroxyphenylalanine in solution forms a non-N-methyl-D-aspartate glutamatergic agonist and neurotoxin

We have investigated the pharmacologic and neurotoxic properties of 2,4,5-trihydroxyphenylalanine [topa; the 6-hydroxylated derivative of 3,4-dihydroxyphenylalanine (dopa)] in central neurons. Application of solutions of topa to the chicken eyecup preparation results in glutamatergic responses mediated predominantly by non-N-methyl-D-aspartate receptors. Pharmacological activity depends upon oxidation in solution to a new compound. This compound is tentatively identified as topa quinone. Solutions of topa are toxic to cortical neurons in culture, and this toxicity is blocked by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. These results suggest that production or accumulation of topa or its oxidation products might be involved in excitotoxicity, especially in dopaminergic neurons and their projection targets.