Actions at sites other than D3 receptors mediate the effects of BP897 on l-DOPA-induced hyperactivity in monoamine-depleted rats

The role of D3 receptors in the antiparkinsonian actions of l-DOPA and l-DOPA-induced dyskinesia (LID) remains unclear. The D3 receptor partial agonist BP897 attenuates LID in primates without affecting the antiparkinsonian actions of l-DOPA, suggesting that “normalization” of D3 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 D3 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 D3 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 D3 receptor antagonist S33084 is not antidyskinetic yet enhances the antiparkinsonian actions of l-DOPA, suggesting that stimulation of D3 receptors is not involved in LID. Here, we address the possibility that in vivo BP897 acts via mechanisms in addition to attenuation of D3 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 D2 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 D3 receptors might be involved in this action.