Noradrenergic modulation of the motor response induced by long-term levodopa administration in Parkinsonian rats

  • Perez V
  • Sosti V
  • Rubio A
 et al. 
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Abstract

A decrease in noradrenergic activity in Parkinson's disease might play a critical role in long-term motor complications associated with chronic dopaminergic replacement. Using the rat model of parkinsonism with an additional noradrenergic degeneration induced by the N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) toxin we evaluated whether the circling motor activity and dose-failure episodes induced by levodopa (L-DOPA) differ between single (6-OHDA) and double (6-OHDA + DSP-4) denervated animals challenged with a single daily dose of L-DOPA. While single-lesioned animals showed a sensitization-desensitization turning response with a significant increase on day 15 and a decrease on day 22, in double-lesioned animals, the turning activity was maximal from day 1 and did not decay on day 22. Double-lesioned rats exhibited significantly higher number of turns on days 15 and 22 and a significantly lower percentage of dose-failure episodes during treatment. Noradrenergic denervation appears to be associated with prolonged long-term dopaminergic sensitization. This type of response appears to be comparable to that in the clinical setting with intermittent L-DOPA administration where no desensitization occurs once the abnormal response is established.

Author-supplied keywords

  • Animals
  • Antiparkinson Agents/pharmacology
  • Benzylamines/toxicity
  • Brain/*drug effects/*metabolism/physiopathology
  • Disease Models, Animal
  • Dopamine/metabolism
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions/physiology
  • Levodopa/*pharmacology
  • Male
  • Movement/drug effects/physiology
  • Neurotoxins/toxicity
  • Norepinephrine/*metabolism
  • Oxidopamine/toxicity
  • Parkinsonian Disorders/*drug therapy/*metabolism/p
  • Presynaptic Terminals/drug effects/metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function/drug effects/physiology
  • Synaptic Transmission/drug effects/physiology
  • Time
  • Treatment Outcome

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Authors

  • V Perez

  • V Sosti

  • A Rubio

  • M Barbanoj

  • I Gich

  • J Rodriguez-Alvarez

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