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

The role of D-3 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 non-nalization 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, 243250]. 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. (c) 2006 Elsevier Inc. All rights reserved.