title: Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain.
abstract: A pathology of brain serotonergic (5-HT) systems has been found in psychiatric disturbances, normal aging and in neurodegenerative disorders including Alzheimer's and Parkinson's disease. Despite the clinical importance of 5-HT, little is known about the endogenous factors that have neurotrophic influences upon 5-HT neurons. The present study examined whether chronic pain parenchymal administration of the neurotrophins 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 micrograms/d) or the control substances (cytochrome c or PBS vehicle) were continuously infused into the rat frontoparietal cortex using an osmotic minipump. One week later, rats were subcutaneously administered PCA (10 mg/kg) or vehicle, and the 5-HT innervation was evaluated after two more weeks of neurotrophin infusion. As revealed with 5-HT immunocytochemistry, BDNF infusions into the neocortex of intact (non-PCA-lesioned) rats caused a substantial increase in 5-HT axon density in a 3 mm diameter region surrounding the cannula tip. In PCA-lesioned rats, intracortical infusions of BDNF completely prevented the severe neurotoxin-induced loss of 5-HT axons near the infusion cannula. In contrast, cortical infusions of vehicle or the control protein cytochrome c did not alter the density of serotonergic axons 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 the 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 PCA-induced loss of 5-HT and 5-HIAA contents and 3H-5-HT uptake near the infusion cannula. Thus, BDNF can promote the sprouting of mature, uninjured serotonergic axons and dramatically enhance the survival or sprouting of 5-HT axons normally damaged by the serotonergic neurotoxin PCA.
authors.affiliation: Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Mamounas
authors.forename: M E
authors.initials: ME
authors.lastname: Blue
authors.forename: J A
authors.initials: JA
authors.lastname: Siuciak
authors.forename: C A
authors.initials: CA
authors.lastname: Altar
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D001921:Brain / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor; D002470:Cell Survival / Q000187:drug effects; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology; D009416:Nerve Regeneration / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D020933:Neurotrophin 3; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism* / Q000493:pharmacokinetics; D010133:p-Chloroamphetamine / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D010133:p-Chloroamphetamine