Blockade of N-methyl-D-aspartate receptors potentiates dopaminergic responses in the 6-OHDA model of Parkinson: differential role of D-1 and D-2 receptors.
The non competitive antagonist of N-methyl-D-aspartate (NMDA) receptors MK-801, at doses which did not produce any behavioural modification per se, increased by about 40% the contralateral turning induced by the dopaminergic (DA) D-1/D-2 agonist L-dopa in rats bearing a unilateral lesion of the DA nigro striatal neurons. Administration of MK-801 in combination with selective agonists of the D-1 (SKF 38393) or D-2 (LY 171555) receptor, induced an increase of about 280% of D-1 mediated turning and a 70% decrease of D-2 mediated turning. Analysis of the potentiation of L-dopa mediated turning by MK-801 after selective D-1 receptor blockade by SCH 23390, revealed that the increase of turning was related to the stimulation of D-1 receptors by L-dopa. Immunocytochemical visualization of the proto-oncogene c-fos in the caudate-putamen (CPu) of lesioned rats, revealed a sparse c-fos positive nuclei in the lesioned CPu of rats treated with SKF 38393 alone, while after combined administration of MK-801 and SKF 38393 dense labelling of nuclei was found. The results indicate that blockade of NMDA receptors by MK-801 acts synergistically with D-1 agonists in the induction of turning after DA denervation and shows that these changes are correlated with c-fos induction in specific areas of the CPu.
Institute of Experimental Pharmacology & Toxicology University of Cagliari, Italy.
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Morelli
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Fenu
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Di Chiara
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D002421:Caudate Nucleus / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D004357:Drug Synergism; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011699:Putamen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016291:Dizocilpine Maleate; D016627:Oxidopamine; D004298:Dopamine