Increased neostriatal dopamine activity after intraperitoneal or intranasal administration of L-DOPA: on the role of benserazide pretreatment.
L-DOPA provides the most potent medication to treat Parkinson's disease, and such systemic treatment is usually combined with a peripheral amino acid decarboxylase inhibitor to amplify its central effectiveness. Since L-DOPA can lose its efficacy or can lead to adverse effects with prolonged application, current pharmacokinetic and dynamic research is aimed at improving the drug's applicability. In a previous study, performed with in vivo microdialysis in the anesthetized rat, we have shown that intranasal L-DOPA administration (without prior decarboxylase inhibition) can increase extracellular dopamine levels in the neostriatum. Using similar experimental conditions in the present experiment, we tested the neurochemical effects of L-DOPA treatment in combination with the peripheral amino acid decarboxylase inhibitor benserazide. In accordance with other data, it was found that the combination of i.p. benserazide and i.p. L-DOPA led to pronounced increases of extracellular levels of dopamine, dihydroxyplenylacetic acid and homovanillic acid in the neostriatum, whereas i.p. L-DOPA alone only moderately increased dopamine, but strongly increased the metabolite levels. Furthermore, increased dopamine levels, and weaker increases of dihydroxyplenylacetic acid and homovanillic acid were observed after i.p. benserazide followed by intranasal L-DOPA. Finally, we found that i.p. benserazide alone can lead to pronounced increases in neostriatal dopamine and moderate increases of dihydroxyplenylacetic acid levels, whereas it did not affect homovanillic acid. Thus, not only the combination of L-DOPA (i.p. or intranasal) with the presumed peripheral L-DOPA decarboxylase inhibitor benserazide, but also each component alone can affect dopamine activity in the brain. Especially the findings with benserazide treatment might be of relevance for understanding the mechanisms of current L-DOPA therapy, since they indicate that part of the treatment's actions may possibly be determined by central dopaminergic effects of the accompanying amino acid decarboxylase inhibitor.
Silva
M A
MA
Institute of Physiological Psychology I, Heinrich-Heine-University of Düsseldorf, Germany.
Mattern
C
C
Häcker
R
R
Tomaz
C
C
Huston
J P
JP
Schwarting
R K
RK
D000281:Administration, Intranasal; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001481:Basal Metabolism; D001545:Benserazide / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D011292:Premedication; D051381:Rats; D017208:Rats, Wistar
D000978:Antiparkinson Agents; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D007980:Levodopa; D001545:Benserazide; D004298:Dopamine