GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR - DISTRIBUTION AND PHARMACOLOGY IN THE RAT FOLLOWING A BOLUS INTRAVENTRICULAR-INJECTION

Glial cell line-derived neurotrophic factor (GDNF) has been shown to i ncrease dopaminergic parameters in vitro and in vivo and can reduce pa rkinsonian behaviors in animal models of the disease. This study deter mined the potential of the lateral ventricle as an administration rout e for GDNF by examining the distribution and neurochemical consequence s of a single intraventricular injection. Autoradiographic analysis sh owed that intraventricularly administered [I-125]GDNF was distributed throughout the ventricular system at 1 and 24 h following injection. T he cerebral cortex, septum, diagonal band, fimbria, striatum, hippocam pus, hypothalamus, substantia nigra/ventral tegmental area, and cerebe llum were also labeled. At 7 days, there was still labeling throughout the ventricular system, hypothalamus, substantia nigra, and cerebellu m. Twenty-four hours following an intrastriatal injection of [I-125]GD NF, label was observed in the substantia nigra/ventral tegmental area, demonstrating retrograde transport. The neurochemical effects of intr aventricularly administered GDNF (0.1-100 mu g) at 7 days post injecti on were also examined. GDNF significantly increased striatal (approxim ately 28%) and nigral (up to 40%) dopamine, as well as regulated the d opamine metabolites homovanillic acid and dihydroxyphenylacetic acid. Dopamine levels were unchanged in the frontal cortex. Dopamine content was significantly increased in the hypothalamus (up to 35%), an incre ase which may contribute to the inhibition of weight gain seen after a dministration of GDNF. Additionally, dopamine turnover was decreased o r unchanged across the brain regions analyzed, which may indicate that in unlesioned rats, intraventricularly administered GDNF stimulates t he synthesis and storage of dopamine. This study shows that intraventr icularly injected GDNF can access basal ganglia structures, most notab ly the midbrain dopamine cell body region, and remains present in this area for at least 7 days following a single administration. GDNF diff erentially increases dopaminergic tone within a variety of brain struc tures, including the nigrostriatal pathway. These data support the pot ential effectiveness of intraventricular administered GDNF as a treatm ent for Parkinson's disease.