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

Abstract

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.