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 D 1 and D 2 receptor subtypes. Therefore, we have investigated the effects of the tyrosine hydroxylase inhibitor α-methyl-p-tyrosine (AMPT) on the actions of D 1 , D 2 , and D 1 /D 2 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 D 1 agonist A-77636 and the D 2 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 D 1 and D 2 receptor stimulation are required for dopamine receptor agonists to produce a maximal antiparkinsonian response. The reversal of motor deficits produced by the mixed D 1 /D 2 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.