2,4,5-Trihydroxyphenylalanine (6-hydroxy-dopa) displaces [3H]AMPA binding in rat striatum.
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.
Cha
J H
JH
Department of Neurology, University of Michigan, Ann Arbor 48109.
Dure LS
I V
IV
Sakurai
S Y
SY
Penney
J B
JB
Young
A B
AB
D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D007608:Kainic Acid / Q000378:metabolism; D007700:Kinetics; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D004295:Dihydroxyphenylalanine; D007051:Ibotenic Acid; D007608:Kainic Acid; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D017981:Receptors, Neurotransmitter; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C001388:6-hydroxydopa