Reversion of levodopa-induced motor fluctuations by the A2A antagonist CSC is associated with an increase in striatal preprodynorphin mRNA expression in 6-OHDA-lesioned rats.
The molecular mechanisms involved in the reversion of levodopa-induced motor fluctuations by the adenosine A2A antagonist 8-(3-chlorostryryl) caffeine (CSC) were investigated in rats with a 6-hydroxydopamine (6-OHDA)-induced lesion and compared with the ones achieved by the kappa-opioid agonist, U50,488. Animals were treated with levodopa (50 mg/kg/day) for 22 days and for one additional week with levodopa + CSC (5 mg/kg/day), levodopa + U50,488 (1 mg/kg/day), or levodopa + vehicle. The reversion of the decrease in the duration of levodopa-induced rotations by CSC, but not by U50,488, was maintained until the end of the treatment and was associated with a further increase in levodopa-induced preprodynorphin mRNA in the lesioned striatum, being higher in the ventromedial striatum. The increase in striatal preprodynorphin expression, particularly in the ventromedial striatum, may be related to the reversion of levodopa-induced motor fluctuations in the CSC-treated animals, suggesting a role of the direct striatal output pathway activity in the ventromedial striatum in the pathophysiology of motor fluctuations.
Laboratori de Neurologia Experimental, Area de Neurociències, Fundació Clínic, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.
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J
Bové
J
J
Serrats
G
G
Mengod
R
R
Cortés
E
E
Aguilar
C
C
Marin
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000241:Adenosine / Q000037:antagonists & inhibitors; D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D002110:Caffeine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004399:Dynorphins / Q000096:biosynthesis* / Q000187:drug effects; D020820:Dyskinesias / Q000209:etiology / Q000503:physiopathology*; D004745:Enkephalins / Q000096:biosynthesis / Q000187:drug effects; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology*; D011498:Protein Precursors / Q000096:biosynthesis* / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists
D018663:Adrenergic Agents; D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; D017473:Receptors, Opioid, kappa; C036448:pre-prodynorphin; C081320:8-(3-chlorostyryl)caffeine; D002110:Caffeine; D007980:Levodopa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins; D016627:Oxidopamine; C033660:preproenkephalin; D000241:Adenosine