Induction of dopamine D-3 receptor expression as a mechanism of behavioral sensitization to levodopa
Induction of dopamine D-3 receptor expression as a mechanism of behavioral sensitization to levodopa
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DOI：
10.1073/pnas.94.7.3363
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发表时间：
1997-04-01
影响因子：
11.1
通讯作者：
Schwartz, JC
中科院分区：
文献类型：
--
作者：
Bordet, R;Ridray, S;Schwartz, JC
在6-羟基多巴胺单侧损毁黑质纹状体多巴胺通路的大鼠上，间接多巴胺受体激动剂左旋多巴的运动刺激效应在反复间歇给药后得到增强。然而，这种行为敏化的机制基本上是未知的。通过原位杂交和7-[H-3]羟基-N，N-二正丙基-2-氨基四氢呋喃放射自显影，分别观察到D-3受体的mRNA和结合部位逐渐出现在失神经支配的尾壳核中，这是一个正常情况下D-3受体亚型缺失的脑区。这两个过程的发展和衰退是以非常平行的时间进程发生的，而D-1或D-2受体的mRNAs没有明显的变化。左旋多巴对D-3受体的诱导是由重复的D-1受体刺激介导的，因为它被拮抗剂SCH 33390和激动剂SKF 38393所阻止，而不是被两种D-2受体激动剂所抑制。左旋多巴的增强行为反应是由新合成的D-3受体介导的，因为在D-3受体诱导之前，低剂量的选择性D-3受体拮抗剂NAFADOTRIDE没有这种作用。D-3受体的诱导和行为敏化还伴随着强啡肽原mRNA水平的持续增强和速激肽原基因表达的进行性下降。我们认为，同一条纹状体黑质运动传出通路释放的强啡肽和P物质之间的失衡与D-3受体的诱导有关，是行为敏感化的原因。
In rats with unilateral lesions of the nigrostriatal dopamine pathway with 6-hydroxydopamine, the motor stimulating effects of levodopa, an indirect dopamine receptor agonist, evidenced by contraversive rotations, become enhanced upon repeated intermittent administration. However, the mechanisms of this behavioral sensitization are essentially unknown. We show that development of sensitization is accompanied by a progressive appearance of D-3 receptor mRNA and binding sites, visualized by in situ hybridization and 7-[H-3]hydroxy-N,N-di-n-propyl-2-aminotetralin autoradiography, respectively, occurring In the denervated caudate putamen, a brain area from which this receptor subtype is normally absent. Development and decay of these two processes occur with closely parallel time courses, whereas there were no marked changes in D-1 or D-2 receptor mRNAs, D-3 receptor induction by levodopa is mediated by repeated D-1 receptor stimulation, since it is prevented by the antagonist SCH 33390 and mimicked by the agonist SKF 38393, but not by two D-2 receptor agonists. The enhanced behavioral response to levodopa is mediated by the newly synthesized D-3 receptor, since it is antagonized by nafadotride, a preferential D-3 receptor antagonist, in low dosage, which has no such effect before D-3 receptor induction. D-3 receptor induction and behavioral sensitization are also accompanied by a sustained enhancement of prodynorphin mRNA level and a progressively decreasing expression of the preprotachykinin gene. We propose that imbalance between dynorphin and substance P release from the same striatonigral motor efferent pathway, related to D-3 receptor induction, is responsible for behavioral sensitization.