Actions at sites other than D(3) 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 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.
Visanji
Naomi P
NP
Toronto Western Research Institute, 399 Bathurst Street, MC11-419, Toronto, Ontario, Canada M5T 2S8.
Millan
Mark J
MJ
Brotchie
Jonathan M
JM
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D015306:Biogenic Monoamines / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy*; D007211:Indoles / Q000494:pharmacology; D007980:Levodopa; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D012110:Reserpine / Q000494:pharmacology; D013997:Time Factors
D018759:Adrenergic Uptake Inhibitors; D015306:Biogenic Monoamines; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D050637:Receptors, Dopamine D3; C120565:BP 897; D007980:Levodopa; C104750:3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole; D012110:Reserpine