The actions of a D-1 agonist in MPTP treated primates show dependence on both D-1 and D-2 receptor function and tolerance on repeated administration.
The potent and long acting D-1 receptor agonist, A-77636 reverses motor deficits in MPTP treated common marmosets following subcutaneous or oral administration. We now explore the effects of acute versus repeated administration of A-77636 and the relative roles of D-1 and D-2 receptor involvement in its antiparkinsonian actions. Acute oral administration (0.18-9.0 mg/kg) or subcutaneous administration (0.036-1.08 mg/kg) of A-77636 produced well co-ordinated bouts of discontinuous locomotor activity. There was no evidence of repetitive or stereotyped movements. However, oral administration of A-77636 (1.44 mg/kg) on alternate days for 10 days produced tolerance to the increase in locomotor activity and improvement of disability. Pretreatment with the D-1 antagonist SCH 23390 (0.625, 2.5 or 5.0 mg/kg, intraperitoneally), produced a dose dependent reduction in locomotor activity and antagonised the reduction in disability scores following administration of A-77636 (0.36 mg/kg, subcutaneously). The inhibitory effects of SCH 23390 lasted for some 2-5 hours after which the activity of A-77636 was gradually restored. Unexpectedly, pretreatment with the D-2 antagonist raclopride (1.25, 5.0 or 20.0 mg/kg, intraperitoneally), dramatically diminished the antiparkinsonian effects of A-77636 (0.36 mg/kg, subcutaneously) in a dose dependent manner. The dependence of the antiparkinsonian activity of A-77636 on intact D-2 receptor function, suggests a need for endogenous D-2 receptor tone to express D-1 mediated locomotor activity.
Smith
L A
LA
Neurodegenerative Disease Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom.
Jackson
M J
MJ
Al-Barghouthy
G
G
Jenner
P
P
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000494:pharmacology*; D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D002144:Callithrix; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D020891:Raclopride / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000037:antagonists & inhibitors; D017448:Receptors, Dopamine D2 / Q000819:agonists*
D001552:Benzazepines; D001578:Benzopyrans; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C079415:A 77636; D020891:Raclopride; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000218:Adamantane