Preservation of a functional nigrostriatal dopamine pathway by GDNF in theintrastriatal 6-OHDA lesion model depends on the site of administration ofthe trophic factor

Here we studied whether glial cell line-derived neurotrophic factor (GDNF), given as a single bolus injection before an intrastriatal 6-hydroxydopamin e (6-OHDA) lesion, can protect the nigrostriatal dopamine neurons against t he toxin-induced damage and preserve normal motor functions in the lesioned animals. GDNF or vehicle was injected in the striatum (25 mug), substantia nigra (25 mug) or lateral ventricle (50 mug) 6 h before the 6-OHDA lesion (20 mug/3 muL). Motor function was evaluated by the stepping and drug-induc ed motor asymmetry tests. Lesioned animals given vehicle alone showed a cle ar ipsilateral-side bias in response to amphetamine (13 turns/min), a moder ate contralateral-side bias to apomorphine (4.5 turns/min) and a moderate t o severe stepping deficit on the contralateral forepaw (three to four steps , as compared with 11-13 steps on the unimpaired side). Injection of GDNF i nto the striatum had a significant protective effect both on nigrostriatal function (1-2 turns/min in the rotation tests and seven to eight steps in t he stepping test), and the integrity of the nigrostriatal pathway, seen as a protection of both the cell bodies in the substantia nigra and the dopami ne innervation in the striatum. Injection of GDNF in the nigra had a protec tive effect on the nigral cell bodies, but not the striatal innervation, an d failed to provide any functional benefit. In contrast, intranigral GDNF h ad deleterious effects on both the striatal TH-positive fibre density and o n drug-induced rotation tests. Intraventricular injection had no effect. We conclude that preservation of normal motor functions in the intrastriatal 6-OHDA lesion model requires protection of striatal terminal innervation, a nd that this can be achieved by intrastriatal, but not nigral or intraventr icular, administration of GDNF.