Altered amantadine effects after repetitive treatment for l-dopa-induced involuntary movements in a rat model of Parkinson's disease

Neurosci Lett. 2023 May 29:806:137248. doi: 10.1016/j.neulet.2023.137248. Epub 2023 Apr 13.

Abstract

Background: l-3,4-dihydroxyphenylalanine (l-dopa) is the most effective drug for Parkinson's disease (PD); however, most PD patients develop motor fluctuations including wearing-off and l-dopa-induced dyskinesia (LID). Amantadine is beneficial for improving the motor symptoms, reducing "off" time, and ameliorating LID, although its long-term efficacy remains unknown.

Objectives: To investigate the effects of amantadine on PD and LID using a rat model with repetitive drug treatment.

Method: We utilized 6-hydroxydopamine injections to develop a hemiparkinsonian rat model. The rats were assigned to four groups: five rats received l-dopa and benserazide for 31 days, six rats received l-dopa and benserazide plus amantadine for 31 days, five rats received l-dopa and benserazide for 15 days followed by l-dopa and benserazide plus amantadine for 16 days, and five rats received l-dopa and benserazide plus amantadine for 15 days followed by l-dopa and benserazide treatment for 16 days. We evaluated the l-dopa-induced abnormal involuntary movements on treatment days 1, 7, 14, 16, 22, and 29. Subsequently, immunohistochemistry for drebrin was performed.

Results: l-dopa-induced abnormal movements were reduced on the first day of amantadine treatment, and these effects disappeared with repetitive treatment. In contrast, the extension of l-dopa "on" time was observed after repetitive amantadine treatment. All groups showed enlarged drebrin immunoreactive dots in the dopamine-denervated striatum, indicating that amantadine did not prevent priming effects of repetitive l-dopa treatment.

Conclusion: Anti-LID effect of amantadine diminished after repetitive treatment, and the effect of amantadine on wearing-off emerged after repetitive treatment in a hemiparkinsonian rat model. Fluctuations in amantadine effects should be considered when using it in clinical settings.

Keywords: 6-hydroxydopamine; Dendritic spine; Dopamine; Drebrin; Dyskinesia; Wearing off.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amantadine / pharmacology
  • Amantadine / therapeutic use
  • Animals
  • Antiparkinson Agents / therapeutic use
  • Benserazide / adverse effects
  • Disease Models, Animal
  • Dyskinesia, Drug-Induced* / drug therapy
  • Levodopa / pharmacology
  • Oxidopamine
  • Parkinson Disease* / drug therapy
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Levodopa
  • Antiparkinson Agents
  • Benserazide
  • Amantadine
  • Oxidopamine