The dopamine D₁ agonist SKF 81297 and the dopamine D₂ agonist LY 171555 act synergistically to stimulate motor behavior of 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine‐lesioned parkinsonian rhesus monkeys

Abstract

At present, the pharmacotherapy of Parkinson's disease (PD) consists mainly of L-dihydroxyphenylalanine (L-DOPA) and/or dopamine D2 receptor agonists. However, in general the clinical efficacy of D2 agonists is less than that of L-DOPA. Therefore, attention is being focussed on the role of the D1 receptor as a target for therapeutic intervention in PD. Recently, we reported that SKF 81297 is a selective D1 agonist that stimulates motor behavior of unilaterally MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned rhesus monkeys. Presently, we studied the effect of coadministration of SKF 81297 and the D2 agonist LY 171555 using the same model of PD. Coadministration of behaviorally active doses of SKF 81297 (0.3 mg/kg) and LY 171555 (0.01 mg/kg) resulted in a prolongation of the motor stimulation induced by either of the drugs alone. Neither administration of SKF 81297, in a dose of 0.03 mg/kg, nor of LY 171555, in a dose of 0.003 mg/kg, were behaviorally active, whereas the combined administration of these compounds induced a significant stimulation of motor behavior. These data suggest that (a) D1 receptor stimulation will prove to be useful in the treatment of PD and (b) better therapeutic results will be obtained by simultaneous stimulation of D1 and D2 receptors as compared with stimulation of both receptors alone.

Actions of the D 1 agonists A-77636 and A-86929 on locomotion and dyskinesia in MPTP-treated L -dopa-primed common marmosets

“…However, combined D 1 and D 2 stimulation may be necessary for an optimal motor response and can produce synergistic responses. Thus, when e¤ective doses of D 1 and D 2 agonists are given simultaneously a prolongation of behavioral e¤ects is produced, while the combined administration of subclinical doses of D 1 and D 2 agonists synergistically stimulates motor behaviour Vermeulen et al 1994;Domino 1997). Such reports, along with the results of the present experiments, indicate that combined administration of D 1 -like and D 2 -like agonist compounds in low doses, with or without L-dopa, may produce enhanced locomotion and be less prone to induce dyskinesia.…”

“…Initial studies with the partial D 1 agonist SKF-38393, which stimulates motor activity in rodents, failed to show antiparkinsonian activity in MPTP-treated monkeys and patients with PD, an outcome ascribed to D 1 antagonism in primates (Close et al 1985;Braun et al 1987;Boyce et al 1990b). More recently, other D 1 agonist compounds, including A-77636, A-86929 (ABT-431), dihydrexidine, CY 208-243, SKF 81297 and SKF 82958, have shown convincing antiparkinsonian activity in the MPTP-treated primate (Temlett et al 1989;Taylor et al 1991;Kebabian et al 1992;Blanchet et al 1993;Gomez-Mancilla et al 1993;Vermeulen et al 1994;Pearce et al 1995;Pearce 1996;Asin et al 1996;Domino 1997;Grondin et al 1997). However, few of these compounds have been studied in patients with PD, with the exceptions of CY 208243, which exhibited some antiparkinsonian activity (Temlett et al 1989;Emre et al 1992) and ABT-431, which has shown comparable motor responses to L-dopa in advanced PD, but with signiÞcantly less dyskinesia (Wright et al 1998).…”

“…The thiobenzoquinoline A-86929 is a selective D 1 agonist compound which is known to produce a robust antiparkinsonian response in animal models of PD, including the MPTP-treated common marmoset Grondin et al 1997;Asin et al 1996). Given the potential of D 1 agonism to enhance the activity of other antiparkinsonian drugs (GomezMancilla et al 1993;Vermeulen et al 1994;Domino 1997) and their favorable e¤ects on dyskinesia in L-dopa-primed animals (Gomez-Mancilla et al 1991;Bédard et al 1993;Blanchet et al 1993Blanchet et al , 1996Pearce et al 1995;Pearce 1996;Grondin et al 1997;), we then investigated the actions of repeated A-77636 on L-dopa-induced dyskinesias in L-dopa-primed MPTPtreated common marmosets when administered directly after subacute L-dopa dosing and then concurrently with L-dopa.…”

Striatal and nigral D 1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats

“…It has been postulated that the poor antiparkinsonian efficacy of SKF 38393 may be due to its relative lack of efficacy in stimulating adenylate cyclase (Watts et al 1993). Indeed, several D 1 selective agonists with full efficacy in stimulating adenylate cyclase have been demonstrated to reduce parkinsonian symptoms in MPTPtreated primates (Taylor et al 1991;Vermulen et al 1994;Akai et al 1995a,b;Gnanalingham et al 1995). The relation between the antiparkinsonian activity of D 1 agonists and their ability to stimulate adenylate cyclase remains unclear, and further research is required to determine whether increasing cyclic-AMP levels is necessary for the antiparkinsonian effects of D 1 agonists.…”

Dopamine D1Receptor Signaling: Does GαQ–Phospholipase C Actually Play a Role?

“…Yet even assuming no metabolism (and these catechols are rapidly metabolized), this yields a predicted concentration at the D 1 receptor far lower than required in vitro to activate either the hypothesized D 1 -PLC or D 1 -D 2 heterodimer systems. More recently, Medvedev et al (2013) concluded that PLCb via D 1 mechanisms regulated forward locomotion in mice, yet the sole experimental selective D 1 agonist, SKF-81297, was used at doses of 10 mg/kg, far higher than the 0.001-0.3 mg/kg known to produce typical D 1 -like behavioral activity (Vermeulen et al, 1994;Cai and Arnsten, 1997;Diaz Heijtz and Castellanos, 2006). A parsimonious deduction would seem to be that D 1 -like behavioral effects are irrelevant to these purported PLC signaling mechanisms requiring near-millimolar concentrations.…”