Microdialysis studies on the action of tolcapone on pharmacologically-elevated extracellular dopamine levels in conscious rats.
To elucidate the importance of catechol-O-methyltransferase, we performed striatal microdialysis studies in conscious rats given tolcapone, an inhibitor of catechol-O-methyltransferase, together with four compounds each of which elevates the extracellular dopamine content through a different mechanism. Tolcapone itself did not alter dopamine levels in the striatal microdialysis fluid but increased DOPAC and decreased homovanillic acid levels. However, tolcapone pretreatment (30 mg/kg) multiplied the already high dopamine levels after levodopa, and less so the moderately elevated dopamine levels after GBR-12909 (at 20 mg/kg) alone, but the minor (insignificant) dopamine-elevating effects of haloperidol and (+)-U232 were not altered. In all cases, a tolcapone pretreatment decreased homovanillic acid levels and elevated DOPAC levels. In further combination studies, GBR-12909 did not alter significantly the effects of levodopa/carbidopa on dopamine, DOPAC and homovanillic acid levels. In these rats, tolcapone enhanced the effect of GBR-12909 on extracellular dopamine but not on DOPAC. In conclusion, when levodopa and carbidopa are given together, COMT inhibition becomes extremely meaningful, and dopamine levels are multiplied by tolcapone. Otherwise, tolcapone is able to further elevate extracellular dopamine levels only when dopamine turnover is normal or low but not when it is high. Overall, the role of COMT in the elimination of synaptic dopamine remains minor compared to the dominance of the reuptake process.
Huotari
M
M
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Gainetdinov
R
R
Männistö
P T
PT
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D002230:Carbidopa / Q000494:pharmacology; D002394:Catechol O-Methyltransferase / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009596:Nitrophenols; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D000077867:Tolcapone; D014793:Visual Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D001577:Benzophenones; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D010879:Piperazines; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C043425:vanoxerine; C045971:UH 232; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase; D006220:Haloperidol; D002230:Carbidopa; D004298:Dopamine; D006719:Homovanillic Acid