Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-D-aspartate neurotoxicity.
The N-methyl-d-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in two- to threefold increases in excitotoxic lesion size. Pre-treatment with a kynurenine 3-hydroxylase inhibitor or with dopamine receptor antagonists, i.e., two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum.
Poeggeler
B
B
Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD 21228, USA.
Rassoulpour
A
A
Wu
H-Q
HQ
Guidetti
P
P
Roberts
R C
RC
Schwarcz
R
R
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism / Q000633:toxicity; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007736:Kynurenic Acid / Q000378:metabolism*; D016202:N-Methylaspartate / Q000378:metabolism / Q000633:toxicity; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000378:metabolism* / Q000633:toxicity; D017378:Quinolinic Acid / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D018491:Dopamine Agonists; D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; D011954:Receptors, Dopamine; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D004298:Dopamine