GDNF reverses priming for dyskinesia in MPTP-treated, L-DOPA-primed commonmarmosets

Parkinson's disease (PD) is associated with a progressive loss of dopamine neurons in the substantia nigra and degeneration of dopaminergic terminals in the striatum. Although L-DOPA treatment provides the most effective symp tomatic relief for PD it does not prevent the progression of the disease, a nd its long-term use is associated with the onset of dyskinesia. In rodent and primate studies, glial cell line-derived neurotrophic factor (GDNF) may prevent 6-OHDA- or MPTP-induced nigral degeneration and so may be benefici al in the treatment of PD. In this study, we investigate the effects of GDN F on the expression of dyskinesia in L-DOPA-primed MPTP-treated common marm osets, exhibiting dyskinesia. GDNF or saline was administered by two intrav entricular injections, 4 weeks apart, to MPTP-treated, L-DOPA-treated commo n marmosets primed to exhibit dyskinesia. Prior to GDNF or saline administr ation, all animals displayed marked dyskinesia when treated with L-DOPA. GD NF administration produced a significant improvement in motor disability an d, following the second injection of GDNF, a significant improvement in the locomotor activity was observed. Following the administration of L-DOPA th ere was a greater reversal of disability and a reduction in the intensity o f L-DOPA-induced dyskinesia in GDNF-treated animals compared to saline-trea ted controls. However, there was no significant difference in L-DOPA's abil ity to increase locomotor activity between GDNF-treated and saline-treated animals. GDNF treatment caused a significant increase in the number of tyro sine hydroxylase-positive neurons in the substantia nigra, but no change in [H-3]mazindol binding to dopamine terminals was found in the striatum of G DNF-treated animals compared to saline-treated controls. In GDNF-treated an imals a small but significant reduction in enkephalin mRNA was observed in the caudate nucleus but not in the putamen or the nucleus accumbens. Substa nce P mRNA expression was equally reduced in the caudate nucleus and the pu tamen of the GDNF-treated animals but not in the nucleus accumbens. Intrave ntricular administration of GDNF improved MPTP-induced disability and rever sed dopamine cell loss in the substantia nigra. GDNF also diminished L-DOPA -induced dyskinesia, which may relate to its ability to partly restore nigr al dopaminergic transmission or to modify the activity of striatal output p athways.