The motor effects of
dopamine D1 receptor activation and the optimal way to stimulate these receptors were studied in a primate model of
parkinsonism induced by the
neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP), using 2 selective full
dopamine D1 receptor agonists:
A-77636 ([1 R,3S] 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1 H-2-
benzopyran hydrochloride), and
SKF 82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrobromide).
A-77636 was administered to one group of primed monkeys (N = 4) previously treated with
levodopa and other
dopamine receptor agonists, while
SKF 82958 was given to another group of
drug-naive monkeys (N = 3). These drugs have different durations of efficacy, lasting > 20 h and approximately 1 h, respectively, and were administered once daily (A-77636) or thrice daily (
SKF 82958) for 7 days. Both drugs demonstrated excellent antiparkinsonian efficacy and locomotor stimulation. However, a rapid, functionally important, homologous (selective for D1 receptor agonists) desensitization process took place as early as on the second day with the longer-acting
drug and a dose escalation of
A-77636 failed to restore the initial benefit. Thrice daily dosing at a 4-h interval with the short-acting agent
SKF 82958 maintained the maximal antiparkinsonian response but some shortening in the duration of response was observed after several days. These behavioral results show that
dopamine D1 receptors are susceptible to desensitization after prolonged occupancy and can be desensitized profoundly and independently of
dopamine D2 receptors in vivo in this model. Potent
dopamine D1 receptor agonists with an intermediate half-life may prove to be better adjuncts in the treatment of
Parkinson's disease. Clinical entities with pathologically enhanced
dopamine D1 receptor-linked neural transmission might eventually also benefit from such desensitization.