3-O-methyl-DOPA is not involved in the development of behavioral supersensitivity after repeated L-dopa administration in 6-OHDA lesioned rats.
The underlying cause of long-term complications of L-DOPA therapy in Parkinson's disease is largely unknown. Recently, centrally and peripherally acting catechol-O-methyltransferase (COMT) inhibitors became available. These drugs are capable of inhibiting the generation of 3-O-methyl-DOPA (3-OMD), a major metabolite of L-dopa developing considerable plasma levels during L-dopa therapy. The use of these drugs offers the opportunity to study the involvement of 3-OMD in the development of behavioral supersensitivity following repeated doses of L-dopa over 11 days in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic system. Repeated daily administration of L-dopa/Carbidopa produced continuous increase of contralateral rotations to both L-dopa/Carbidopa and to challenge doses of apomorphine. This increase was not influenced by peripherally and peripherally plus centrally acting COMT inhibitors, OR-462 and OR-486, respectively, administered simultaneously with L-dopa/Carbidopa. Both COMT inhibitors suppressed the L-dopa induced increase of 3-OMD plasma levels, OR-486 being more effective than OR-462. This indicates that 3-OMD is not involved in the development of behavioral supersensitivity following repeated L-dopa treatment in rats with unilateral 6-OHDA lesion of the nigrostriatal system.
Bräutigam
K
K
Institute of Pharmacology and Toxicology of Medical Faculty [Charité], Humboldt University at Berlin, Germany.
Sohr
R
R
Morgenstern
R
R
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002230:Carbidopa / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D003342:Corpus Striatum / Q000187:drug effects*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008750:Methyldopa / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects*; D013239:Stereotyped Behavior / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects*
D065098:Catechol O-Methyltransferase Inhibitors; D011954:Receptors, Dopamine; D007980:Levodopa; D008750:Methyldopa; D016627:Oxidopamine; D002230:Carbidopa; D001058:Apomorphine