Blockade of A2A receptors plus l-DOPA after nigrostriatal lesion results in GAD67 mRNA changes different from l-DOPA alone in the rat globus pallidus and substantia nigra reticulata.
Studies in animal models of Parkinson's disease (PD) suggest the potential utility of adenosine A(2A) antagonists in the treatment of this disease. In the present study, unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats received chronic intermittent treatment with the adenosine A(2A) antagonist SCH58261 (5 mg/kg) plus l-DOPA (3 mg/kg) or l-DOPA (6 mg/kg) alone, at doses producing the same intensity of contralateral turning on first administration. Three days after discontinuation of treatments, GABA synthesizing enzyme glutamic acid decarboxylase (GAD67) mRNA was evaluated at cellular level in the globus pallidus (GP) and substantia nigra pars reticulata (SNr) by in situ hybridization. 6-OHDA lesion significantly increased GAD67 mRNA levels in both the GP and SNr ipsilateral to the lesion. Chronic l-DOPA (6 mg/kg), in contrast to SCH58261 plus l-DOPA (3 mg/kg), produced a sensitized contralateral turning indicative of dyskinetic potential and further increased GAD67 mRNA in the GP. In the SNr, a significant decrease in GAD67 mRNA was observed after either treatments. However, while l-DOPA (6 mg/kg) decreased SNr GAD67 mRNA below the intact side, SCH58261 plus l-DOPA (3 mg/kg) brought GAD67 mRNA to the same level of the intact SNr. l-DOPA (3 mg/kg) or SCH58261 (5 mg/kg) alone failed to modify GAD67 mRNA. Results suggest that an increase in GAD67 mRNA in GP and a decrease in SNr might underlie dyskinetic movements induced by chronic l-DOPA. In contrast, the lack of GAD67 mRNA changes in the GP and a less marked inhibition of SNr might correlate with the absence of dyskinetic potential observed after SCH58261 plus l-DOPA.
Carta
Anna R
AR
Department of Toxicology and Centre of Excellence for Neurobiology of Dependence, University of Cagliari, 09124 Cagliari, Italy.
Tabrizi
Mojgan Aghazadeh
MA
Baraldi
Pier G
PG
Pinna
Annalisa
A
Pala
Paola
P
Morelli
Micaela
M
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D003342:Corpus Striatum / Q000293:injuries; D005917:Globus Pallidus / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000187:drug effects*; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000187:drug effects*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects
D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D007527:Isoenzymes; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D007980:Levodopa; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1