Differential therapeutic effects of dopamine D1 and D2 agonists in MPTP-induced parkinsonian monkeys: clinical implications.
L-DOPA, the precursor of dopamine, remains most effective in the treatment of patients with Parkinson's disease, but prolonged L-DOPA treatment often produces adverse effects, including dyskinesia and psychosis. Dopamine receptors can be divided into two major subtypes, D1 and D2. Might both subtypes of the dopamine receptor be equally relevant to amelioration of parkinsonian symptoms and responsible for the adverse side effects? To address this question, the effects of D1 or D2 receptor agonists alone and in joint administration were examined in MPTP-induced parkinsonian monkeys. The parkinsonian symptoms, such as tremor, bradykinesia and rigidity, and the adverse side effects, such as hyperactivity and aggressiveness, were evaluated independently using different behavioral criteria. The results showed that antiparkinsonian effects can be exerted either by the D1 agonist (SKF 82958) alone or by the D2 agonist (quinpirole) alone, whereas hyperactivity and aggressiveness manifested by dopamine agonists require coactivation of the D1 and D2 receptors. Thus, the antiparkinsonian effect can be dissociated from the adverse effect by therapeutic strategy. It is implied that imbalances in activation of the D1 and D2 receptors may provide a favorable approach for long-term treatment of parkinsonian patients with dopamine drugs.
Kuno
S
S
Department of Neurology, Utano National Hospital, Kyoto, Japan. sakuno21@mbox.kyoto-inet.or.jp
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001058:Apomorphine / Q000627:therapeutic use; D001552:Benzazepines / Q000627:therapeutic use; D018491:Dopamine Agonists / Q000627:therapeutic use*; D008252:Macaca fascicularis; D010302:Parkinson Disease, Secondary / Q000188:drug therapy* / Q000209:etiology; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D017448:Receptors, Dopamine D2 / Q000819:agonists*
D000978:Antiparkinson Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C071262:SK&F 82958; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D001058:Apomorphine