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Effect of High Single Doses of Levodopa and Carbidopa on Brain Dopamine and Its Metabolites: Modulation by Selective Inhibitors of Monoamine Oxidase and/or catechol-O-methyltransferase in the Male Rat

Effect of High Single Doses of Levodopa and Carbidopa on Brain Dopamine and Its Metabolites: Modulation by Selective Inhibitors of Monoamine Oxidase and/or catechol-O-methyltransferase in the Male Rat

P T Männistö, P Tuomainen

Naunyn Schmiedebergs Arch Pharmacol. 1991 Oct;344(4):412-8.

PMID: 1766471

Abstract:

The upper limits of striatal and hypothalamic dopamine formation and metabolism in the rat were defined after acute levodopa/carbidopa (100/100 mg/kg) in combination with MAO (clorgyline; 32 mg/kg or pargyline; 100 mg/kg) and/or COMT inhibitors (OR-462, OR-611, Ro 41-0960, 30 mg/kg). Striatal and hypothalamic dopa and 3-OMD levels increased several hundred times after levodopa/carbidopa treatment alone. Dopamine, DOPAC, HVA and 3-MT levels elevated also but noradrenaline and 5-HT did not. Clorgyline further increased 3-OMD, dopamine and 3-MT concentrations while DOPAC and HVA levels decreased. These changes were even more pronounced after pargyline. In the striatum, all COMT inhibitors (with levodopa/carbidopa) blocked 3-OMD formation but elevated neither dopamine nor DOPAC levels. OR-462 increased dopa levels. Only Ro 41-0960, the brain penetrating compound, blunted HVA levels. All three COMT inhibitors decreased high 3-OMD levels evoked by MAO inhibitors (+ levodopa/carbidopa). In pargyline-treated rats, COMT inhibitors did not alter dopamine, DOPAC or HVA levels but all of them decreased significantly 3-MT levels, particularly Ro 41-0960. Striatal dopamine levels increased maximally 6 times compared to those in the saline-treated controls. In the hypothalamus, COMT inhibitors decreased 3-OMD levels to 1/5-1/30 of those after levodopa/carbidopa alone. COMT inhibitors suppressed 3-OMD formation also in clorgyline and pargyline (+ levodopa/carbidopa) treated rats. After clorgyline, OR-611 and Ro 41-0960 increased high dopamine levels but only Ro 41-0960 suppressed HVA and 3-MT levels. None of the COMT inhibitors changed the high dopamine and low DOPAC levels after pargyline.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP125628979	Ro 41-0960		125628-97-9	Price

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