Exendin-4 treatment enhances L-DOPA evoked release of striatal dopamine and decreases dyskinetic movements in the 6-hydoxydopamine lesioned rat

Abstract

Objectives To determine whether the glucagon-like 1 peptide analogue exendin-4 (EX-4) augments the neurochemical effects of a single L-DOPA treatment and whether EX-4 can decrease L-DOPA induced dyskinesias (LIDS). Methods Rats were lesioned with 6-hydroxydopamine (6-OHDA) and 7 days later given EX-4 for 7 days. The following day, rats were given L-DOPA and extracellular dopamine was measured. The animals were then killed to determine tissue dopamine. To study LIDS, EX-4 and/or L-DOPA were co-administered daily, 7 days after 6-OHDA. LIDS were determined on Days 2, 4, 8, 12 and 16 prior to neurochemical assessment. Key findings EX-4 reduced 6-OHDA induced damage. Acute effects of L-DOPA were potentiated by EX-4 in lesioned rats. Treatments with EX-4 caused a progressive reduction in LIDS. Conclusions EX-4 treatment potentiates the effects of a single dose of L-DOPA. This augmentation indicates that lower L-DOPA doses might be used to the same effect in patients. The reduction in LIDS suggests that co-treatment with EX-4 could allow the use of L-DOPA with fewer side-effects and possibly therefore allow earlier introduction of L-DOPA in the clinic.