Article date: 1991/10/28
PubMed ID: 1664920
Journal name: Neuroscience letters (ISSN: 0304-3940)
Excitatory amino acid (EAA) receptor-mediated events have recently been implicated in dopaminergic mechanisms of neurotoxicity. 2,4,5-Trihydroxyphenylalanine (6-hydroxy-DOPA, TOPA), the ortho-hydroxylated derivative of the dopamine precursor 2,4-dihydroxyphenylalanine (L-DOPA), has recently been reported to have neurotoxic properties which are blocked by CNQX, a specific antagonist of the AMPA class of non-N-methyl-D-aspartate (non-NMDA) EAA receptors. We report here that 6-hydroxy-DOPA is a selective displacer of [3H]AMPA binding in rodent brain. 6-Hydroxy-DOPA was as potent as kainate in displacing [3H]AMPA binding, with an IC50 value of 32 microM. Ineffective displacers of [3H]AMPA binding included dopamine, 6-hydroxydopamine, L-DOPA, D-DOPA, carbidopa, DOPAC, beta-methylamino-L-alanine, 2,4-dihydroxyphenylacetyl-L-asparagine, homogentisic acid, 2,4-dihydroxyphenylacetic acid, amantadine, and threo-DOPS. 6-Hydroxy-DOPA (100 microM) also displaced 20% of [3H]kainate binding, but did not displace binding to NMDA, phencyclidine (PCP), or dopaminergic (D1 and D2) receptors. These data raise the possibility that 6-hydroxy-DOPA or another abnormal metabolite of L-DOPA could act as an excitotoxic agent via action at AMPA receptors. Given that non-NMDA receptors are postulated to play a role in neurotoxic events, these data provide an additional mechanism via which EAA receptor-mediated events could produce neurodegeneration in areas of brain with dopaminergic innervation.
Author List: Cha J H, Dure LS I V, Sakurai S Y, Penney J B, Young A B
Publication Types: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
Substances mentioned in the article: Receptors, AMPA; Receptors, Kainic Acid; Receptors, Neurotransmitter; Tritium; 6-hydroxydopa; Ibotenic Acid; Dihydroxyphenylalanine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Kainic Acid;
Mesh terms: Animals; Autoradiography; Binding, Competitive; Corpus Striatum/metabolism; Dihydroxyphenylalanine/analogs & derivatives; Ibotenic Acid/analogs & derivatives; Kainic Acid/metabolism; Kinetics; Radioligand Assay; Rats; Receptors, AMPA; Receptors, Kainic Acid; Receptors, Neurotransmitter/drug effects; Tritium; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid;