Benserazide dosing regimen affects the response to L-3,4-dihydroxyphenylalanine in the 6-hydroxydopamine-lesioned rat

Behav Pharmacol. 2012 Apr;23(2):126-33. doi: 10.1097/FBP.0b013e32834f9f82.

Abstract

Peripheral aromatic amino acid decarboxylase (AADC) inhibitors, such as benserazide, are routinely used to potentiate the effects of L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease (PD) and in experimental models of PD. However, there is little information available on the optimal dose or the timing of administration relative to L-DOPA treatment. We now assess the effect of dose, timing, and supplemental administration of benserazide on the rotational response induced by L-DOPA in unilateral 6-hydroxydopamine-lesioned rats. L-DOPA (12.5 mg/kg, p.o.) concomitant with benserazide (3.125-15 mg/kg, p.o.) produced a dose-dependent increase in contraversive rotation compared with the effects of L-DOPA alone. The optimal L-DOPA response was achieved with 10 mg/kg of benserazide and this dose was used in subsequent experiments. When L-DOPA treatment was delayed for 1, 2, or 3 h after benserazide, the rotational response declined suggesting loss of AADC inhibition. Unexpectedly, there was also a progressive decline in response when benserazide and L-DOPA were given together but at increasingly later time points of 08.00, 09.00, 10.00, and 11.00 h. To assess supplemental administration of benserazide, an additional dose was given 2 h after the initial benserazide/L-DOPA treatment. This produced a further increase in the number of contralateral rotations indicating that the effect of benserazide declines while plasma levels of L-DOPA are maintained. Therefore, optimization of the dose and timing of benserazide administration is essential to achieve a consistent L-DOPA response in 6-hydroxydopamine-lesioned rats. These findings may have implications for the way in which peripheral AADC inhibitors are used in the treatment of PD.

MeSH terms

  • Animals
  • Aromatic Amino Acid Decarboxylase Inhibitors
  • Benserazide / administration & dosage
  • Benserazide / pharmacology*
  • Dose-Response Relationship, Drug*
  • Drug Administration Schedule*
  • Enzyme Inhibitors / pharmacology
  • Levodopa / administration & dosage
  • Levodopa / agonists*
  • Male
  • Microinjections
  • Motor Activity / drug effects*
  • Oxidopamine / administration & dosage
  • Rats
  • Rats, Wistar
  • Time Factors

Substances

  • Aromatic Amino Acid Decarboxylase Inhibitors
  • Enzyme Inhibitors
  • Levodopa
  • Benserazide
  • Oxidopamine