Concomitant short- and long-duration response to levodopa in the 6-OHDA-lesioned rat: a behavioural and molecular study.
The long-duration response (LDR) is a sustained improvement in parkinsonism due to chronic levodopa therapy and lasts after discontinuation of treatment. We have investigated the molecular changes that underlie the LDR in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion. Animals were treated for 22 days with levodopa or saline. Forelimb akinesia was evaluated prior and following a test dose of levodopa. Rotational behaviour was weekly evaluated. Levodopa induced an improvement in the parkinsonian limb akinesia that lasted for 48 h after withdrawal. A shortening in the duration of rotational behaviour was observed. After 3 days of washout, levodopa treatment maintained elevated striatal preproenkephalin mRNA expression, also inducing an increase in preprodynorphin (PDyn) and dopamine D-3 receptor mRNAs, but without any modification of the adenosine A(2A) mRNA expression induced by 6-OHDA. Levodopa reversed the lesion-induced increase in the expression of cytochrome oxidase mRNA in the subthalamic nucleus and glutamate decarboxylase mRNA in the pars reticulata of the substantia nigra. After 7 days of levodopa washout, the molecular markers show a decline in the basal ganglia evolving towards the parkinsonian state, being statistically significant for the striatal PDyn mRNA. This study characterizes the concomitant presence of the short-duration response and LDR to levodopa in the 6-OHDA model of parkinsonism and shows that the molecular changes induced by levodopa in the basal ganglia are not permanent and that this reversal after levodopa washout may be responsible for the gradual motor deterioration that characterize the LDR.
Marin
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C
Laboratori de Neurologia Experimental, Area de Neurociències, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. cmarin@medicina.ub.es
Aguilar
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E
Mengod
G
G
Cortés
R
R
Obeso
J A
JA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001930:Brain Injuries / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015259:Dopamine Agents / Q000627:therapeutic use*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016627:Oxidopamine; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D013997:Time Factors
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D007980:Levodopa; D016627:Oxidopamine