The neurotrophins NT-4/5 and BDNF augment serotonin, dopamine, and GABAergic systems during behaviorally effective infusions to the substantia nigra.
Brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) have both been identified as ligands for the TrkB receptor, yet differences have emerged in terms of their in vitro potencies for neuronal survival and differentiation. This has prompted the in vivo study of their effects on behavior and neuro-chemical parameters associated with dopamine, serotonin, and GABAergic neurons in the basal ganglia. Two-week supranigral infusions of NT-4/5 and BDNF were similar in their ability to augment levels of the dopamine metabolite homovanilic acid (HVA) (63 and 78%, respectively) and the ratios of dihydroxphenylacetic acid/dopamine (DOPAC/DA) (39, 48%) and HVA/DA (85, 77%) in the caudate-putamen of the hemisphere ipsilateral to the nigral infusion. Striatal concentrations of DOPAC were elevated 45% by BDNF but not by NT-4/5. The 3-MT/dopamine ratio, an indicator of dopamine release, was elevated by 38 and 32% in the striata of BDNF- and NT-4/5-infused rats, respectively. Striatal indoleamine metabolism, determined by the ratio of 5-hydroxyindoleacetic acid (5HIAA)/serotonin was also elevated by NT-4/5 and BDNF in the caudate-putamen (29, 32%), and the 5HIAA content of the substantia nigra was elevated by both factors (43, 40%). The activity of GAD within the superior colliculus was elevated 21 and 41% by BDNF and NT-4/5, respectively. A contraversive rotational bias was induced in BDNF and NT-4/5-treated rats challenged with d-amphetamine, and these responses were blocked by pretreatment with selective D1 or D2 receptor antagonists but not by opiate receptor antagonism. Thus, NT-4/5 and BDNF can elevate the turnover of dopamine through both metabolic and release pools and augment the behavioral response to d-amphetamine. The role for dopamine in this behavioral response is indicated by the requirement of unoccupied D1 and D2 receptors, but may also involve changes in serotonergic, GABAergic, or other pathways. The TrkB receptor-specific actions of BDNF and NT-4/5 may have implications for understanding the etiology or treatment of basal ganglia disorders.
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Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591.
Boylan
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Fritsche
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Jackson
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Hyman
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor; D004298:Dopamine / Q000502:physiology*; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000502:physiology*; D013239:Stereotyped Behavior; D013378:Substantia Nigra / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; C071951:neurotrophin 5; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; C073922:neurotrophin 4; D004298:Dopamine