Chronic intranigral administration of brain-derived neurotrophic factor produces striatal dopaminergic hypofunction in unlesioned adult rats and fails to attenuate the decline of striatal dopaminergic function following medial forebrain bundle transection.
The present study determined the effects of chronic intranigral injections of recombinant human brain-derived neurotrophic factor (1 micrograms) every second day for 19 days on the functional capacity of dopaminergic neurons of the nigrostriatal pathway of unlesioned adult rats. In animals chronically treated with brain-derived neurotrophic factor, we observed amphetamine (5 mg/kg)-induced circling behavior directed toward the neurotrophin-injected side (33 turns/5 min). The behavioral asymmetry was paralleled by reductions of striatal [3H]dopamine uptake (27%), tyrosine hydroxylase activity (68%), dopamine content (36%) and [3H]mazindol binding site density (35%) on the same side as brain-derived neurotrophic factor treatment. While chronic injections of brain-derived neurotrophic factor produced a modest decrease in the number of tyrosine hydroxylase-positive cell bodies in the vicinity of the injection site, a similar reduction in cell number was observed in animals injected with a control protein, cytochrome c. However, in contrast to the animals treated with brain-derived neurotrophic factor, rats treated with the control protein showed no amphetamine-induced circling behavior, and there were no significant reductions in neurochemical parameters of striatal dopaminergic function. Lastly, we found that in brain-derived neutrophic factor-injected animals there was a 30% decrease of tyrosine hydroxylase messenger RNA levels in the ventral mesencephalon. We also determined the effects of brain-derived neurotrophic factor treatment on animals with transections of the medial forebrain bundle. Medial forebrain bundle-lesioned animals challenged with amphetamine circled (55 turns/5 min) ipsilateral to the lesioned side. The medial forebrain lesions decreased the following markers of striatal dopaminergic function: [3H]opamine uptake (65%), tyrosine hydroxylase activity (79%), dopamine content (80%) and [3H]mazindol binding site density (52%), induced a pronounced loss of tyrosine hydroxylase-positive cell bodies within the substantia nigra and also reduced tyrosine hydroxylase messenger RNA levels. Chronic intranigral brain-derived neurotrophic factor treatment did not attenuate nor did it exacerbate the medial forebrain bundle lesion-induced decreases of dopaminergic parameters in either the substantia nigra or striatum. The results of the present study indicate that chronic intranigral administration of brain-derived neurotrophic factor to normal adult rats induces a dopaminergic hypofunction in the striatum which is manifested behaviorally by amphetamine-induced rotations. The brain-derived neurotrophic factor-induced striatal function is not the result of significant cell loss at the levels of the substantia nigra, but seems to be related to brain-derived neurotrophic factor-induced down-regulation of dopaminergic-specific proteins.(ABSTRACT TRUNCATED AT 400 WORDS)
Lapchak
P A
PA
Division of Neurogerontology, Andrus Gerontology Center, University of Southern California, Los Angeles 90089-0191.
Beck
K D
KD
Araujo
D M
DM
Irwin
I
I
Langston
J W
JW
Hefti
F
F
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D019208:Brain-Derived Neurotrophic Factor; D003342:Corpus Striatum / Q000033:anatomy & histology / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D005260:Female; D007150:Immunohistochemistry; D007267:Injections; D008454:Mazindol / Q000378:metabolism; D008474:Medial Forebrain Bundle / Q000033:anatomy & histology / Q000502:physiology*; D008636:Mesencephalon / Q000378:metabolism; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D008454:Mazindol; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine