The present study determined the effects of intraventricularly administered glial cell line-derived neurotrophic factor on the behavioral and neurochemical sequelae of unilateral excitotoxic lesions of the striatum. Distinct asymmetrical relational behavior in response to peripheral administration of amphetamine (5 mg/kg) was noted one and two weeks following injections of quinolinic acid (200 nmol) into two sites in the left striatum. In rats given a single intraventricular injection of glial cell line-derived neurotrophic factor (10-1000 mu g) 30 min before the toxin, amphetamine-induced rotational behavior was significantly attenuated. Analysis of Nissl-stained coronal sections showed marked neuronal loss in the striatum ipsilateral to the quinolinic acid injections, which was al least partially prevented by glial cell line-derived neurotrophic factor. D-1 and D-2 dopamine binding sites in the striatum, the majority of which are localized to subpopulations of GABAergic neurons, were decreased to a similar extent by quinolinic acid. Moreover, the reduction was attenuated by glial cell line-derived neurotrophic factor treatment to a similar degree, suggesting that the two subpopulations of GABAergic striatal output neurons are equally vulnerable to excitotoxic damage. Concomitant changes in neurotransmitter function as a result of the lesion were also observed: [H-3]GABA uptake into striatal target tissues (globus pallidus and substantia nigra) was considerably reduced in the lesioned compared to the contralateral unlesioned tissues, as were [H-3]choline and [H-3]dopamine uptake into striatal synaptosomes. Similarly, striatal choline acetyltransferase activity was decreased by the lesion. Decrements in neuropeptide levels of similar magnitude were evident ipsilateral to the lesion; substance P, met-enkephalin and dynorphin A contents in the globus pallidus and substantia nigra were significantly reduced. Striatal somatostatin and neuropeptide Y levels were not altered. All of the neurochemical deficits induced by striatal quinolinic acid lesions were attenuated by intraventicular delivery of glial cell line-derived neurotrophic factor. Continuous intraventricular infusion of this trophic factor (10 mu g/day) over a two-week period did not afford notable improvement compared to the single injection of 10 mu g. In contrast, continuous infusion of brain-derived neurotrophic factor (10 mu g/day) directly into the striatum did not affect any of the neurochemical parameters studied. However, neurotrophin-3 (10 mu g/day) delivery into the striatum significantly increased [H-3]GABA uptake, but only modestly affected [H-3]choline uptake. The results indicate that glial cell line-derived neurotrophic factor counteracts neuronal damage induced by a striatal excitotoxic insult and support its potential use as a treatment for central nervous system disorders that may be a consequence of excitotoxic processes, such as Huntington's disease. (C) 1997 IBRO. Published by Elsevier Science Ltd.
