The dopamine D1 agonist SKF 81297 and the dopamine D2 agonist LY 171555 act synergistically to stimulate motor behavior of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian rhesus monkeys.
At present, the pharmacotherapy of Parkinson's disease (PD) consists mainly of L-dihydroxyphenylalanine (L-DOPA) and/or dopamine D2 receptor agonists. However, in general the clinical efficacy of D2 agonists is less than that of L-DOPA. Therefore, attention is being focussed on the role of the D1 receptor as a target for therapeutic intervention in PD. Recently, we reported that SKF 81297 is a selective D1 agonist that stimulates motor behavior of unilaterally MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned rhesus monkeys. Presently, we studied the effect of coadministration of SKF 81297 and the D2 agonist LY 171555 using the same model of PD. Coadministration of behaviorally active doses of SKF 81297 (0.3 mg/kg) and LY 171555 (0.01 mg/kg) resulted in a prolongation of the motor stimulation induced by either of the drugs alone. Neither administration of SKF 81297, in a dose of 0.03 mg/kg, nor of LY 171555, in a dose of 0.003 mg/kg, were behaviorally active, whereas the combined administration of these compounds induced a significant stimulation of motor behavior. These data suggest that (a) D1 receptor stimulation will prove to be useful in the treatment of PD and (b) better therapeutic results will be obtained by simultaneous stimulation of D1 and D2 receptors as compared with stimulation of both receptors alone.
Graduate School Neurosciences Amsterdam, Vrije Universiteit, The Netherlands.
R J
RJ
Vermeulen
B
B
Drukarch
M C
MC
Sahadat
C
C
Goosen
E C
EC
Wolters
J C
JC
Stoof
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004873:Ergolines / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009048:Motor Skills / Q000187:drug effects* / Q000502:physiology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000503:physiopathology*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D019257:Quinpirole; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000502:physiology; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology
D001552:Benzazepines; D018491:Dopamine Agonists; D004873:Ergolines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019257:Quinpirole; C067113:SK&F 81297; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine