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.