Co-administration of the partial dopamine D2 agonist terguride with L-dopa attenuates L-dopa-induced locomotor sensitization in hemiparkinsonian mice.
While dopamine replacement remains the standard pharmacotherapy for Parkinson's disease, chronic L-dopa treatment is associated with development of debilitating motor fluctuations such as L-dopa-induced dyskinesia (LID). In this study we evaluated the effects of the partial dopamine D(2) agonist terguride on the development of LID in hemiparkinsonian mice (unilaterally lesioned with 6-hydroxydopamine). First, consistent with the partial agonist property, terguride had 1000-fold higher potency than dopamine, yet producing one-third level of maximal activation of dopamine, as assayed by [(35)S]GTPgammaS binding. Furthermore, in the absence and presence of dopamine in vitro, terguride increased and decreased striatal [(35)S]GTPgammaS binding, respectively. Next, we found that co-administration of terguride (at 0.1 and 0.5mg/kg, i.p.) with L-dopa (1.8 mg/kg) daily for 14 days, significantly attenuated the development and expression of L-dopa-induced rotational sensitization. Furthermore, the cross-challenge paradigm revealed that chronic L-dopa treatment (but not terguride) sensitized locomotor response to the dopamine D(1) agonist SKF 81297 while chronic treatment with terguride (but not L-dopa) produced sensitized locomotor responses to the adenosine A(2A) antagonist 8-(3-chlorostyryl)caffeine (CSC). Importantly, the co-administration of terguride with L-dopa did not show locomotor sensitization to either SFK 81297 or CSC upon challenge. Together, these results suggest that co-administration of partial dopamine D(2) agonists with L-dopa may prophylactically attenuate L-dopa-induced abnormal behavioral responses such as LID.
Kalda
Anti
A
Department of Pharmacology, University of Tartu, Ravila 19, 51014 Tartu, Estonia.
Herm
Laura
L
Rinken
Ago
A
Zharkovsky
Alexander
A
Chen
Jiang-Fan
JF
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001552:Benzazepines / Q000008:administration & dosage; D002110:Caffeine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003342:Corpus Striatum / Q000187:drug effects; D018491:Dopamine Agonists / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007980:Levodopa / Q000008:administration & dosage* / Q000009:adverse effects; D008090:Lisuride / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D011897:Random Allocation; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D013462:Sulfur Radioisotopes
D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013462:Sulfur Radioisotopes; C081320:8-(3-chlorostyryl)caffeine; C006208:dironyl; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002110:Caffeine; D007980:Levodopa; C067113:SK&F 81297; D016627:Oxidopamine; D008090:Lisuride