Dopamine D-1 receptor desensitization profile in MPTP-lesioned primates

The motor effects of dopamine D-1 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 D-1 receptor agonists: A-77636 ([1R,3S] 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran hydrochloride), and SKF 82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-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 D-1 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 D-1 receptors are susceptible to desensitization after prolonged occupancy and can be desensitized profoundly and independently of dopamine D-2 receptors in vivo in this model. Potent dopamine D-1 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 D-1 receptor-linked neural transmission might eventually also benefit from such desensitization.