Behavioral involvement of central dopamine D1 and D2 receptors in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys.
To clarify the roles of dopamine D1 and D2 receptors in behavioral symptoms of Parkinson's disease, antiparkinsonian effects of various dopamine agonists in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian monkeys were investigated with regard to induction of hyperactivity such as excitability, irritability and aggressiveness. The non-selective dopamine agonist apomorphine ameliorated the parkinsonism, but induced marked hyperactivity dose-dependently. Pretreatment with either the dopamine D1 antagonist SCH 23390 or the dopamine D2 antagonist sulpiride markedly suppressed the apomorphine-induced hyperactivity with slight attenuation of the antiparkinsonian effects. Both the dopamine D2-receptor agonist quinpirole and the dopamine D1-receptor agonist SKF 82958 ameliorated the parkinsonism in a dose-dependent manner with a slight induction of hyperactivity. Combination treatment of a threshold dose of quinpirole with that of SKF 82958 augmented the antiparkinsonian effects without a marked induction of hyperactivity. However, the combination treatment at higher doses induced marked hyperactivity accompanied by augmented antiparkinsonian effects. These results suggest that stimulation of either central dopamine D1 or D2 receptors is requisite for the antiparkinsonian effects and concurrent strong stimulation of both central dopamine D1 and D2 receptors causes marked hyperactivity which may be predictive of dopaminergic psychiatric side effects.
Akai
T
T
Research Department, Nihon Schering K.K., Osaka, Japan.
Ozawa
M
M
Yamaguchi
M
M
Mizuta
E
E
Kuno
S
S
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008252:Macaca fascicularis; D010302:Parkinson Disease, Secondary; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D013469:Sulpiride / Q000494:pharmacology; D013997:Time Factors
D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013469:Sulpiride; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D001058:Apomorphine