The role of D(3) receptors in the antiparkinsonian actions of
l-DOPA and
l-DOPA-induced
dyskinesia (LID) remains unclear. The D(3) receptor partial agonist BP897 attenuates LID in primates without affecting the antiparkinsonian actions of
l-DOPA, suggesting that "normalization" of D(3) activity is antidyskinetic [Bezard, E., Ferry, S., Mach, U., Stark, H., Leriche, L., Boraud, T., Gross, C., and Sokoloff, P., 2003. Attenuation of
levodopa-induced
dyskinesia by normalizing
dopamine D(3) receptor function.
Nat. Med. 9, 762-767]. However, subsequent studies have questioned these findings [Hsu, A., Togasaki, D.M., Bezard, E., Sokoloff, P., Langston, J.W., Di Monte, D.A., and Quik, M., 2004. Effect of the D(3)
dopamine receptor partial agonist BP897 [N-[4-(4-(2-
methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on l-3,4-dihydroxyphenylalanine-induced
dyskinesias and
parkinsonism in squirrel monkeys. J. Pharmacol. Exp. Ther. 311, 770-777]. The D(3) receptor antagonist
S33084 is not antidyskinetic yet enhances the antiparkinsonian actions of
l-DOPA, suggesting that stimulation of D(3) receptors is not involved in LID. Here, we address the possibility that in vivo BP897 acts via mechanisms in addition to attenuation of D(3) signaling.
l-DOPA (125 mg/kg) elicits
hyperkinesia in
reserpine-treated rats, the vertical component of which (rearing) is attenuated by agents with antidyskinetic actions in
MPTP-lesioned primates and
Parkinson's disease (PD) [Johnston, T.H., Lee, J., Gomez-Ramirez, J., Fox, S.H., and Brotchie, J.M., 2005. A simple rodent assay for the in vivo identification of agents with potential to reduce
levodopa-induced
dyskinesia in
Parkinson's disease. Exp. Neurol. 191, 243-250]. BP897 (0.1, 0.3, 1.0 and 3 mg/kg) reduced
l-DOPA-induced rearing by 0%, 44%, 86% and 57% respectively. In contrast,
S33084 had no effect on
l-DOPA-induced rearing (0.1 mg/kg, 115%; 0.3 mg/kg, 94%, 1 mg/kg, 134%; 3 mg/kg, 100%, of vehicle, all P > 0.05). Furthermore,
S33084 failed to antagonize the effects of BP897 on
l-DOPA-induced rearing. The influence of BP897 on
l-DOPA-induced rearing was, however, mimicked by the selective D(2) antagonist L741,626. Finally, BP897 attenuated
l-DOPA-induced horizontal activity, an action attenuated by
S33084 and mimicked by L741,626. Thus, while BP897 may reduce LID, we raise the possibility that receptors other than D(3) receptors might be involved in this action.