Enhanced [3H]DOPA and [3H]dopamine turnover in striatum and frontal cortex in vivo linked to glutamate receptor antagonism.
We tested the hypothesis that blockade of NMDA glutamate receptors in brain enhances dopamine turnover. We blocked this class of glutamate receptors in the rat brain in vivo with dizocilpine (MK-801) and measured the accumulation of radiolabeled DOPA and its metabolites as functions of time after intravenous bolus injection. Using the time courses of the accumulated metabolites, we calculated the turnover constants of enzymes mediating dopamine synthesis and catabolism. Dizocilpine treatment for 8 days enhanced the rates of DOPA decarboxylation and dopamine oxidation (monoamine oxidation) 4- and 16-fold, respectively, in neostriatum and 10- and 3-fold, respectively, in frontal cortex. The findings are not inconsistent with the hypothesis that the psychotomimetic properties of dizocilpine may be the manifestation of denervation hypersensitivity linked to activation of key enzymes of dopamine turnover in striatum.
Reith
J
J
Positron Imaging Laboratories, McConnell Brain Imaging Center, Montreal Neurological Institute, Quebec, Canada.
Cumming
P
P
Gjedde
A
A
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005625:Frontal Lobe / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium
D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D014316:Tritium; D004295:Dihydroxyphenylalanine; D016291:Dizocilpine Maleate; D004298:Dopamine