Endogenous dopaminergic tone and dopamine agonist action.
Dopamine receptor agonists provide symptomatic relief in the early stages of Parkinson's disease, but with disease progression, their efficacy decreases. The reason behind this decrease in effectiveness is unknown, but maximal efficacy may be dependent on endogenous dopaminergic tone to provide stimulation of D1 and D2 receptor subtypes. Therefore, we have investigated the effects of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT) on the actions of D1, D2, and D1/D2 agonists and levodopa (L-dopa) in common marmosets treated with 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Administration of AMPT alone further increased motor disability and decreased locomotor activity. Administration of L-dopa reversed motor disability and increased locomotor activity, and this reversal was not affected by previous AMPT treatment. The D1 agonist A-77636 and the D2 agonist quinpirole reversed motor deficits, but these effects were markedly inhibited by previous AMPT treatment. Administration of quinpirole with A-77636 produced a reversal of motor deficits that was more resistant to AMPT pretreatment than was the effect produced by quinpirole or A-77636 alone. These data suggest that D1 and D2 receptor stimulation are required for dopamine receptor agonists to produce a maximal antiparkinsonian response. The reversal of motor deficits produced by the mixed D1/D2 agonist apomorphine was more resistant to AMPT treatment than that produced by quinpirole or A-77636. However, the motor effects of A-77636 plus quinpirole and of apomorphine were still affected by AMPT treatment. This suggests that loss of tyrosine hydroxylase activity may also alter motor activity through inhibition of endogenous L-dopa or norepinephrine synthesis, because both are also involved in the genesis of motor activity.
Treseder
S A
SA
Neurodegenerative Disease Research Centre, Guy's, King's, and St. Thomas's School of Biomedical Sciences, King's College London, UK.
Smith
L A
LA
Jenner
P
P
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects*; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002144:Callithrix; D015259:Dopamine Agents / Q000009:adverse effects / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D005260:Female; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D019257:Quinpirole / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors*; D019805:alpha-Methyltyrosine / Q000009:adverse effects*
D000978:Antiparkinson Agents; D001578:Benzopyrans; D015259:Dopamine Agents; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C079415:A 77636; D019257:Quinpirole; D007980:Levodopa; D019805:alpha-Methyltyrosine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D000218:Adamantane