Romero J, Berrendero F, Pérez-Rosado A, Manzanares J, Rojo A, Fernández-Ruiz J J, de Yebenes J G, Ramos J A
Instituto Universitario de Drogodependencias, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
Life Sci. 2000;66(6):485-94. doi: 10.1016/s0024-3205(99)00618-9.
It has been recently suggested that the effects of cannabinoids on motor behavior might be different in rats with lesions of nigrostriatal dopaminergic neurons than in controls. In the present study, we examined the possible alteration in the status of cannabinoid CB1 receptors in the basal ganglia of rats with unilateral lesions of those neurons caused by 6-hydroxydopamine. We used two different experimental groups depending on the duration of the period of recovery after the lesion, and comparisons were done between the lesioned and nonlesioned sides at the level of the basal ganglia. Both groups of lesioned rats exhibited a similar marked reduction in tyrosine hydroxylase (TH)-mRNA levels, measured by in situ hybridization, in the substantia nigra of the lesioned side. In the same way, lesioned rats exhibited the characteristic rotational behavior after a single injection of apomorphine and the intensity of this rotation was stable at the two times analyzed after the lesion. Also as expected, lesioned rats exhibited an increase in proenkephalin mRNA levels in the caudate-putamen, whereas mRNA levels of substance P decreased, although differences between the two times of recovery analyzed were observed in this case. We did not find any significant changes in CB1 receptor binding, measured by [3H]WIN-55,212,2 autoradiography, or in the activation of signal transduction mechanisms, measured by WIN-55,212,2-stimulated [35S]GTPgammaS binding autoradiography, between the lesioned and nonlesioned sides at the level of the lateral caudate-putamen, globus pallidus and substantia nigra in both groups of lesioned rats. However, we found a significant increase in levels of CB1 receptor-mRNA transcripts, measured by in situ hybridization, in the lesioned side in both the lateral and medial caudate-putamen. This occurred 7-10 weeks after the lesion, but the increase was markedly waned after 17-18 weeks. In summary, the unilateral 6-hydroxydopamine lesion of nigrostriatal dopaminergic neurons originated a marked increase in CB1 receptor-mRNA levels in cell bodies of striatal efferent neurons, although accompanied by no changes in CB1 receptor binding and activation of signal transduction mechanisms. This supports a critical role for dopamine in the control of CB1 receptor gene expression. However, the magnitude of the effect significantly waned as a function of the duration of the period after lesion.
最近有人提出，大麻素对运动行为的影响在黑质纹状体多巴胺能神经元受损的大鼠中可能与对照组不同。在本研究中，我们研究了由6-羟基多巴胺导致的单侧神经元损伤大鼠基底神经节中大麻素CB1受体状态的可能改变。根据损伤后恢复时间的长短，我们使用了两个不同的实验组，并在基底神经节水平上对损伤侧和未损伤侧进行了比较。两组损伤大鼠损伤侧黑质中通过原位杂交测量的酪氨酸羟化酶（TH）-mRNA水平均出现了类似的显著降低。同样，损伤大鼠在单次注射阿扑吗啡后表现出特征性的旋转行为，并且这种旋转的强度在损伤后的两次分析中保持稳定。同样如预期的那样，损伤大鼠尾状核-壳核中前脑啡肽mRNA水平升高，而P物质的mRNA水平降低，尽管在这种情况下观察到两次恢复时间之间存在差异。在两组损伤大鼠的外侧尾状核-壳核、苍白球和黑质水平上，我们未发现通过[3H]WIN-55,212,2放射自显影测量的CB1受体结合或通过WIN-55,212,2刺激的[35S]GTPγS结合放射自显影测量的信号转导机制激活在损伤侧和未损伤侧之间有任何显著变化。然而，我们通过原位杂交测量发现，外侧和内侧尾状核-壳核的损伤侧CB1受体-mRNA转录本水平显著升高。这种情况发生在损伤后7-10周，但在17-18周后这种升高明显减弱。总之，黑质纹状体多巴胺能神经元的单侧6-羟基多巴胺损伤导致纹状体传出神经元细胞体中CB1受体-mRNA水平显著升高，尽管CB1受体结合和信号转导机制的激活没有变化。这支持了多巴胺在控制CB1受体基因表达中的关键作用。然而，随着损伤后时间的延长，这种效应的程度显著减弱。
