Lapchak P A, Beck K D, Araujo D M, Irwin I, Langston J W, Hefti F
Division of Neurogerontology, Andrus Gerontology Center, University of Southern California, Los Angeles 90089-0191.
Neuroscience. 1993 Apr;53(3):639-50. doi: 10.1016/0306-4522(93)90612-j.
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)
本研究确定了每隔一天向成年未损伤大鼠黑质内注射重组人脑源性神经营养因子（1微克），持续19天，对黑质纹状体通路多巴胺能神经元功能的影响。在用脑源性神经营养因子长期治疗的动物中，我们观察到苯丙胺（5毫克/千克）诱导的向注射神经营养因子一侧的转圈行为（33转/5分钟）。行为不对称伴随着纹状体[3H]多巴胺摄取量（27%）、酪氨酸羟化酶活性（68%）、多巴胺含量（36%）以及[3H]麦角乙脲结合位点密度（35%）在与脑源性神经营养因子治疗同侧的降低。虽然长期注射脑源性神经营养因子使注射部位附近酪氨酸羟化酶阳性细胞体数量略有减少，但在注射对照蛋白细胞色素c的动物中也观察到了类似的细胞数量减少。然而，与用脑源性神经营养因子治疗的动物不同，用对照蛋白治疗的大鼠未表现出苯丙胺诱导的转圈行为，纹状体多巴胺能功能的神经化学参数也没有显著降低。最后，我们发现，在注射脑源性神经营养因子的动物中，腹侧中脑酪氨酸羟化酶信使核糖核酸水平降低了30%。我们还确定了脑源性神经营养因子治疗对内侧前脑束横断动物的影响。内侧前脑束损伤的动物在受到苯丙胺刺激时向损伤侧的同侧转圈（55转/5分钟）。内侧前脑束损伤降低了纹状体多巴胺能功能的以下指标：[3H]多巴胺摄取量（65%）、酪氨酸羟化酶活性（79%）、多巴胺含量（80%）以及[3H]麦角乙脲结合位点密度（52%），导致黑质内酪氨酸羟化酶阳性细胞体明显减少，同时也降低了酪氨酸羟化酶信使核糖核酸水平。长期黑质内注射脑源性神经营养因子既没有减轻也没有加重内侧前脑束损伤诱导的黑质或纹状体中多巴胺能参数的降低。本研究结果表明，向正常成年大鼠长期黑质内注射脑源性神经营养因子会在纹状体中诱导多巴胺能功能减退，这在行为上表现为苯丙胺诱导的旋转。脑源性神经营养因子诱导的纹状体功能改变不是黑质水平显著细胞丢失的结果，而是似乎与脑源性神经营养因子诱导的多巴胺能特异性蛋白下调有关。（摘要截断于400字）
