Different Patterns of Behavior and Gene Expression Induced by Chronic L-Dopa and A2A Antagonists Plus L-Dopa Treatments in 6- Hydroxydopamine Lesioned Rats

Abstract

Several studies in experimental models of Parkinson’s disease (PD) have proposed adenosine A2A antagonists as an effective therapy for PD. In the present study, unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats were injected chronically with L-3,4-dihydroxyphenyl-alanine (L-DOPA) (6 mg/kg), or with the adenosine A2A antagonist SCH 58261 (5 mg/kg) plus L-DOPA (3 mg/kg), and levels of GAD67, dynorphin and enkephalin mRNA were measured in the striatum. As previously reported, L-DOPA (6 mg/kg) and SCH 58261 (5 mg/kg) plus L-DOPA (3 mg/kg) produced the same degree of turning behavior after the first administration. However, whereas L-DOPA (6 mg/kg) induced a sensitized turning behavior during the treatment, predictive of a dyskinetic potential, SCH 58261 (5 mg/kg) plus L-DOPA (3 mg/kg) produced a stable turning behavior response which could suggest the absence of dyskinetic side effects. Following 6-OHDA lesion, GAD67 and enkephalin mRNAs were elevated in the striatum, whereas dynorphin mRNA was decreased. Chronic intermittent L-DOPA (6 mg/kg) induced an increase in the levels of GAD67, dynorphin and enkephalin mRNA in the lesioned striatum as compared to the vehicle treatment. By contrast, L-DOPA (3 mg/kg), SCH 58261 (5 mg/kg) plus L-DOPA (3 mg/kg), or SCH 58261 (5 mg/kg) alone, failed to produce any significant modification in striatal mRNA levels as compared to vehicle. Changes in GAD67, dynorphin and enkephalin mRNA levels suggest that L-DOPA (6 mg/kg), but not SCH 58261 plus L-DOPA (3 mg/kg), produces long-lasting alterations in the activity of striatal efferent neurons.