Differential effects of D1 and D2 agonists in MPTP-treated primates: functional implications for Parkinson's disease.
Administration of the indirect agonist L-dopa, the nonselective direct agonist apomorphine, or the selective D2 agonist (+)-PHNO, reversed parkinsonism and induced locomotor activation in MPTP-treated squirrel monkeys. In contrast, administration of the selective partial D1 agonist SKF38393 did not induce locomotor activity, but rather decreased activity. Choreiform movements were observed only following treatment with L-dopa. Coadministration of the D1 antagonist SCH23390 prevented L-dopa-induced chorea at the time of peak effect. However, a rebound exaggeration of chorea was observed following SCH 23390 at the time when chorea induced by L-dopa alone would normally be subsiding. Unlike chorea, dystonia could be induced by treatment with either L-dopa or (+)-PHNO. Administration of apomorphine failed to significantly induce dystonia, although a small increase was observed with the highest dose. Treatment with SKF38393 actually decreased dystonia. Our findings clearly indicate that D2 receptor stimulation appears essential for antiparkinsonian activity, and also implicate D2 receptors in the genesis of dystonia, but not chorea. D1 receptor stimulation appears to be involved in the genesis of chorea and possibly also dystonia.
Boyce
S
S
Merck Sharp & Dohme Research Laboratories, Harlow, England.
Rupniak
N M
NM
Steventon
M J
MJ
Iversen
S D
SD
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000502:physiology; D010078:Oxazines / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012453:Saimiri
D001552:Benzazepines; D010078:Oxazines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C042631:naxagolide; D007980:Levodopa; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D001058:Apomorphine