GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR AUGMENTS MIDBRAIN DOPAMINERGIC CIRCUITS IN-VIVO

Recently, a novel glial cell line-derived neurotrophic factor (GDNF) h as been identified, cloned, and shown to have potent survival- and gro wth-promoting activity on fetal rat midbrain dopaminergic neurons in c ell culture. In this study, we document marked and long-lasting effect s on adult rat midbrain dopaminergic neurons in vivo after intracrania l administration. A single injection of this factor into the substanti a nigra elicited a dose-dependent increase in both spontaneous and amp hetamine-induced motor activity, and a decrease in food consumption, l asting 7-10 days. Using immunocytochemistry, we found sprouting of tyr osine hydroxylase-positive neurites towards the injection site, and in creased tyrosine hydroxylase immunoreactivity of the ipsilateral stria tum was produced by GDNF. There was also a marked and dose-dependent i ncrease in dopamine turnover in the substantia nigra and striatum, and in ipsilateral dopamine levels in the substantia nigra. Little or no effects of GDNF were seen on norepinephrine or serotonin levels. The n eurochemical changes on dopaminergic afferents persist for at least 3 weeks after a single intracranial injection of 10 mu g. Taken together , these data suggest that this glial cell line-derived factor has a po tent influence on adult rat dopamine neurons and may have a potentiall y important role as a trophic factor for these neurons.