Kobayashi S, Ogren S O, Hoffer B J, Olson L
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Exp Neurol. 1998 Dec;154(2):302-14. doi: 10.1006/exnr.1998.6952.
To determine the differences in behavioral effects between intrastriatal and intracerebroventricular glial cell-derived neurotrophic factor (GDNF) administration, spontaneous locomotor activity was measured after intrastriatal or intracerebroventricular injection of GDNF (10 microg) in normal adult rats with implanted guide cannulae. In addition, the distribution of GDNF after intracerebral injection was studied immunohistochemically. Intrastriatal administration of GDNF significantly increased rearing behavior 3-4 h after injection. Increases in all three aspects of locomotor activity (motility, locomotion, and rearing) were most pronounced 3 days after intrastriatal injection, and they lasted for several days. This hyperactivity was blocked by the selective dopamine D1 receptor antagonist SCH22390 and by the selective D2 receptor antagonist raclopride at doses of the dopamine receptor antagonists, which by themselves did not affect spontaneous locomotor activity. These results suggest that GDNF has both acute and long-lasting pharmacological effects on dopamine neurons in adult animals and stimulates locomotor activity by activating both dopamine D1 and D2 receptors. On the other hand, intracerebroventricular administration of the same dose of GDNF failed to increase locomotor activity at any time during the test period (12 days). The immunohistochemical study demonstrated widespread distribution of GDNF in the entire body of the striatum within 24 h after intrastriatal injection. It also revealed deep penetration of GDNF from the ventricular space into the brain parenchyma after intracerebroventricular injection. GDNF-immunoreactive neuronal cell bodies were seen in the ipsilateral substantia nigra pars compacta most frequently 6 h after intrastriatal injection. The number of such cell bodies after intracerebroventricular administration, on the other hand, was much lower than that seen after intrastriatal administration. Taken together, these data suggest that intrastriatal administration of GDNF is an effective approach for affecting DA transmission. Long-lasting behavior effects are mediated via dopamine D1 and D2 receptors. Higher doses of GDNF would probably be needed using the intracerebroventricular route as compared to intraparenchymal delivery to exert effects on the nigrostriatal system in Parkinson's disease patients.
为了确定纹状体内和脑室内注射胶质细胞源性神经营养因子（GDNF）后行为效应的差异，在植入引导套管的正常成年大鼠中，纹状体内或脑室内注射GDNF（10微克）后测量自发运动活性。此外，采用免疫组织化学方法研究了脑内注射后GDNF的分布情况。纹状体内注射GDNF后3 - 4小时显著增加了竖毛行为。纹状体内注射后3天，运动活性的所有三个方面（运动性、移动性和竖毛）的增加最为明显，且持续数天。这种多动行为被选择性多巴胺D1受体拮抗剂SCH22390和选择性D2受体拮抗剂雷氯必利阻断，多巴胺受体拮抗剂的剂量本身并不影响自发运动活性。这些结果表明，GDNF对成年动物的多巴胺神经元具有急性和持久的药理作用，并通过激活多巴胺D1和D2受体来刺激运动活性。另一方面，在测试期（12天）内的任何时间，脑室内注射相同剂量的GDNF均未能增加运动活性。免疫组织化学研究表明，纹状体内注射后24小时内GDNF广泛分布于整个纹状体。脑室内注射后还显示GDNF从脑室空间深入脑实质。纹状体内注射后6小时，在同侧黑质致密部最常观察到GDNF免疫反应性神经元细胞体。另一方面，脑室内给药后此类细胞体的数量远低于纹状体内给药后。综上所述，这些数据表明纹状体内注射GDNF是影响多巴胺传递的有效方法。持久的行为效应是通过多巴胺D1和D2受体介导的。与实质内给药相比，帕金森病患者使用脑室内途径可能需要更高剂量的GDNF才能对黑质纹状体系统产生作用。
