Brain-derived neurotrophic factor augments rotational behavior and nigrostriatal dopamine turnover in vivo.
Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor (NGF)-related family of neutrophins, promotes the survival and differentiation of cultured nigral dopamine neurons. Two-week infusions of BDNF were made above the right pars compacta of the substantia nigra in adult rats. Systemic injection of these animals with (+)-amphetamine, a dopamine-releasing drug, induced 3 or 4 body rotations per minute directed away from the nigral infusion site. Neither supranigral NGF nor neocortical BDNF infusions induced rotational behavior. Systemic injections of the postsynaptic dopamine receptor agonist apomorphine did not induce rotations in these animals, demonstrating a presynaptic dopamine neuron locus for BDNF action. In support of this, neostriatal levels of the dopamine metabolite homovanillic acid (HVA) were elevated by 28%, and the HVA/dopamine and dihydroxyphenylacetic acid (DOPAC)/dopamine ratios were elevated by 56% and 34%, respectively, in the BDNF-infused brain hemisphere. BDNF augmented striatal concentrations of HVA and DOPAC and the metabolite/dopamine ratios to even greater extents after (+)-amphetamine injection, when peak rotational effects occurred. Intrastriatal infusions of BDNF produced fewer rotations per minute (1-2.5) after (+)-amphetamine and smaller elevations in HVA and the HVA/dopamine ratio (15% and 30%, respectively) than after supranigral delivery. Neither striatal dopamine, gamma-aminobutyric acid, nor acetylcholine high-affinity uptake or the synthetic enzymes for these neurotransmitters was altered by BDNF. These behavioral and neurochemical effects demonstrate an action of BDNF on dopamine neurons in vivo and are consistent with a potential role for BDNF in the treatment of Parkinson disease.
Altar
C A
CA
Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
Boylan
C B
CB
Jackson
C
C
Hershenson
S
S
Miller
J
J
Wiegand
S J
SJ
Lindsay
R M
RM
Hyman
C
C
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012399:Rotation
D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D000661:Amphetamine; D001058:Apomorphine; D004298:Dopamine; D006719:Homovanillic Acid