BRAIN-DERIVED NEUROTROPHIC FACTOR PROMOTES THE SURVIVAL AND SPROUTINGOF SEROTONERGIC AXONS IN RAT-BRAIN

A pathology of brain serotonergic (5-HT) systems has been found in psy chiatric disturbances, normal aging and in neurodegenerative disorders including Alzheimer's and Parkinson's disease. Despite the clinical i mportance of 5-HT, little is known about the endogenous factors that h ave neurotrophic influences upon 5-HT neurons. The present study exami ned whether chronic brain parenchymal administration of the neurotroph ins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or NGF could prevent the severe degenerative loss of serotonergic axons normally caused by the selective 5-HT neurotoxin p- chloroamphetamine (PCA). The neurotrophins (5-12 mu g/d) or the control substances (cyto chrome c or PBS vehicle) were continuously infused into the rat fronto parietal cortex using an osmotic minipump. One week later, rats were s ubcutaneously administered PCA (10 mg/kg) or vehicle, and the 5-HT inn ervation was evaluated after two more weeks of neurotrophin infusion. As revealed with 5-HT immunocytochemistry, BDNF infusions into the neo cortex of intact (non-PCA-lesioned) rats caused a substantial increase in 5-HT axon density in a 3 mm diameter region surrounding the cannul a tip. In PCA-lesioned rats, intracortical infusions of BDNF completel y prevented the severe neurotoxin-induced loss of 5-HT axons near the infusion cannula. In contrast, cortical infusions of vehicle or the co ntrol protein cytochrome c did not alter the density of serotonergic a xons in intact animals, nor did control infusions prevent the loss of 5-HT axons in PCA-treated rats. NT-3 caused only a modest sparing of t he 5-HT innervation in PCA-treated rats, and NGF failed to prevent the loss of 5-HT axon density. The immunocytochemical data were supported by neurochemical evaluations which showed that BDNF attenuated the PC A-induced loss of 5-HT and 5-HIAA contents and H-3-5-HT uptake near th e infusion cannula. Thus, BDNF can promote the sprouting of mature, un injured serotonergic axons and dramatically enhance the survival or sp routing of 5-HT axons normally damaged by the serotonergic neurotoxin PCA.