Entacapone potentiates the long-duration response but does not normalize levodopa-induced molecular changes.
Coadministration of entacapone with levodopa attenuates motor complications in experimental models of Parkinson's disease. The mechanisms underlying entacapone effects are unknown. We investigated the effect of entacapone, on: long-duration response (LDR) to levodopa, levodopa-induced postsynaptic pharmacodynamic mechanisms and molecular changes in hemiparkinsonian rats. 6-Hydroxydopamine-unilaterally lesioned rats were treated with levodopa (25 mg/kg)+vehicle; levodopa+entacapone (30 mg/kg) or saline, twice daily for 22 days. The LDR and the apomorphine-induced rotations were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin and dopamine D-3 receptor mRNAs, subthalamic cytochrome oxidase mRNA and nigral glutamic acid decarboxylase mRNA. Entacapone potentiated the LDR but did not modify either the apomorphine-induced rotational behavior or the molecular changes. Our results suggest that the effects of entacapone on levodopa-induced motor response are not mediated by postsynaptic mechanisms and that administration of entacapone is not able to normalize the molecular alterations induced by levodopa in the basal ganglia.
Marin
C
C
Laboratori de Neurologia Experimental, Area de Neurociències, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. cmarin@clinic.ub.es
Aguilar
E
E
Mengod
G
G
Cortés
R
R
Rodríguez-Oroz
M C
MC
Obeso
J A
JA
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D002396:Catechols / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D004399:Dynorphins / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics; D004745:Enkephalins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000235:genetics; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007980:Levodopa / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000235:genetics; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology; D020530:Subthalamus / Q000187:drug effects / Q000503:physiopathology
D000978:Antiparkinson Agents; D002396:Catechols; D004745:Enkephalins; D009570:Nitriles; D011498:Protein Precursors; D012333:RNA, Messenger; D050637:Receptors, Dopamine D3; C036448:pre-prodynorphin; D007980:Levodopa; C071192:entacapone; D004399:Dynorphins; C033660:preproenkephalin; D003576:Electron Transport Complex IV; D005968:Glutamate Decarboxylase; D001058:Apomorphine