Is stimulation of D1 and D2 dopamine receptors important for optimal motor functioning in Parkinson's disease?

Although the function of D-2-like receptors is known, the function of D-1-like receptors in the treatment of Parkinson's disease remains to be determined. Some but not all D-1-agonist drugs reverse motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates and exert an anti-Parkinsonian activity in man. Various types of D-1 receptors may be present in the brain or the same receptor may be linked to different transduction mechanisms and this may explain the inconsistences in drug action. Short-acting D-2 agonists [quinpirole, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO)] induce dyskinesia in MPTP-treated monkeys while longer-acting compounds (bromocriptine, ropinirole) have less ability to do so. There is little information on the ability of D-1 agonists to induce dyskinesia in drug-naive MPTP-treated monkeys but some compounds (CY-208243 and SKF-82958) produce abnormal movements. In MPTP-treated primates primed with L-3,4-dihydroxyphenylalanine (L-DOPA) to exhibit dyskinesia, all D-2-agonist drugs induce dyskinesia. In contrast, D-1-agonist compounds evoke less dyskinesia, and on repeated administration long-acting D-1 agonist drugs reverse or abolish dyskinesia. Dyskinesia induced by L-DOPA is associated with an imbalance between striatal output pathways leading to altered neuronal activity in the medial pallidal segment. Evidence from 6-hydroxydopamine-lesioned rats, MPTP-treated monkeys and patients with Parkinson's disease suggests that chronic L-DOPA treatment leads to an alteration in the activity of the D-2-mediated strio-pallidal gamma-aminobutyric acid (GABA) enkephalin-containing pathway. In a recent study in normal monkeys treated with very high doses of L-DOPA for 3 months, the onset of dyskinesia was again associated with altered activity of this pathway. In contrast, L-DOPA treatment reverses lesion-induced alterations in the D-1-mediated strio-pallidal/nigral GABA preprotachykinin (substance P)-containing pathway and in normal animals is without effect. D-1 agonism may produce an anti-Parkinsonian response and reduce the intensity of established dyskinesia. In addition, D-1 agonism may reduce the incidence of nausea and vomiting, lessen psychotic episodes, improve cognitive function and reverse impaired bladder function in Parkinson's disease.