N-methyl-D-aspartate receptor antagonist and dopamine D1 and D2 agonist interactions in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced hemiparkinsonian monkeys

EF Domino and J Sheng

Department of Pharmacology, University of Michigan, Ann Arbor.

The noncompetitive N-methyl-D-aspartate antagonist (5R,10S)-(+)-5- methyl- 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) and three dopamine agonists [(+/-)6-chloro-7,8- dihydroxy-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepin e hydrobromide (SKF-81297), (+/-)6,chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine hydrobromide (SKF-82958) selective for D1 and (-)-2-[N-propyl-N-(2-thienyl)ethyl-amino-5- hydroxytetralin] hydrochloride (N-0923) selective for D2 receptors] were studied in seven adult female hemiparkinsonian Macaca nemestrina monkeys. Video recordings of free circling behavior showed that both SKF-82958 and N- 0923 produced dose-related mean increases in contraversive rotations during the 120-min period after i.m. injection. SKF-81297 (21.1, 67.8 and 210.7 micrograms/kg) was relatively inactive compared to SKF-82958 (24.8, 74.8 and 234 micrograms/kg). The selective D2 agonist N-0923 (3.2, 10 and 32 micrograms/kg, i.m.) was the most potent in producing contraversive circling behavior. The noncompetitive N-methyl-D- aspartate antagonist dizocilpine (MK-801), in doses of 10 and 32 micrograms/kg i.m., produced a very slight increase in contraversive circling in contrast to the selective dopamine agonist SKF-82958. A large dose (100 micrograms/kg, i.m.) of MK-801 produced marked central nervous system depression. In combination with the dopamine agonists N- 0923 and SKF-82958, MK-801 depressed contraversive circling in all doses studied. This study using hemiparkinsonian monkeys does not support the suggestion that a noncompetitive N-methyl-D-aspartate antagonist such as MK-801 would be useful in adjunctive therapy of human Parkinson's disease.

Volume 264, Issue 1, pp. 221-225, 01/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

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