L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA

Eur J Neurosci. 1998 Aug;10(8):2694-706.


Rats sustaining unilateral near-complete 6-hydroxydopamine lesions of the mesostriatal dopamine pathway received daily injections of 3, 4 dihydroxyphenyl-l-alanine (L-DOPA, 8 mg/kg plus 15 mg/kg benserazide) for 3 weeks. During this period, about 50% of the rats gradually developed abnormal involuntary movements, lasting for 2-3 h following each L-DOPA dose. Rats were killed 3 days after the last L-DOPA injection, and sections through the striatum were processed for in situ hybridization histochemistry. Within the L-DOPA-treated group, levels of preproenkephalin (PPE) mRNA, glutamic acid decarboxylase (GAD67) mRNA, and prodynorphin (PDyn) mRNA in the dopamine-denervated caudate-putamen, as well as GAD67 mRNA expression in the globus pallidus ipsilateral to the 6-hydroxydopamine (6-OHDA) lesion, were higher in dyskinetic than non-dyskinetic animals, and positively correlated with the rats' dyskinesia scores. By contrast, striatal preprotachykinin mRNA expression and D2 receptor-radioligand binding were not significantly associated with dyskinesia. Among all these markers, PDyn mRNA levels showed the most pronounced treatment-dependence (three times higher in the L-DOPA-treated group than in saline-injected lesion-only controls), and the strongest correlation with the rats' dyskinesia scores (r2 = 0.82). However, a multiple regression equation including the three factors, GAD67 mRNA levels in the GP, GAD67 mRNA in the lateral CPu, and striatal PDyn mRNA, gave a better fit for dyskinesia scores than PDyn mRNA alone (r2 = 0.92). The results show that L-DOPA-induced dyskinesia is associated with overexpression of PDyn and GAD67 mRNA in the striatal projection neurons, and GAD67 mRNA levels in the globus pallidus. Due to its treatment-dependent expression, and strong correlation with the associated dyskinetic symptoms, striatal PDyn mRNA, in particular, may play a role in the mechanisms of behavioural sensitization brought about by the drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoradiography
  • Behavior, Animal / drug effects
  • Corpus Striatum / drug effects
  • Corpus Striatum / enzymology
  • Corpus Striatum / metabolism*
  • Dyskinesia, Drug-Induced / metabolism*
  • Enkephalins / genetics*
  • Female
  • Gene Expression Regulation / drug effects
  • Glutamate Decarboxylase / genetics*
  • In Situ Hybridization
  • Levodopa / pharmacology*
  • Oxidopamine / pharmacology
  • Protein Precursors / genetics*
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / metabolism
  • Tachykinins / genetics


  • Enkephalins
  • Protein Precursors
  • RNA, Messenger
  • Receptors, Dopamine D2
  • Tachykinins
  • preprotachykinin
  • Levodopa
  • Oxidopamine
  • preproenkephalin
  • Glutamate Decarboxylase