Bi-directional effects of GABAB receptor agonists on the mesolimbic dopamine system
Bi-directional effects of GABAB receptor agonists on the mesolimbic dopamine system
复制标题
DOI：
10.1038/nn1181
复制
发表时间：
2004-02-01
影响因子：
25
通讯作者：
Lüscher, C
中科院分区：
文献类型：
--
作者：
Cruz, HG;Ivanova, T;Lüscher, C
滥用药物的奖赏效应是通过中脑边缘多巴胺系统的激活介导的，而中脑边缘多巴胺系统被假定的抗渴望化合物所抑制。有趣的是，不同的 GABA(B) 受体激动剂可以对奖赏途径产生类似的相反作用，但所涉及的细胞机制尚不清楚。在这里，我们发现，G蛋白门控内向整流钾（GIRK，Kir3）通道与GABA（B）受体的耦合功效（EC50）在多巴胺神经元中比在腹侧被盖区（VTA）的GABA神经元中低得多，这取决于GIRK亚基的差异表达。因此，在啮齿动物 VTA 切片中，低浓度的经典激动剂巴氯芬会导致活性增加，而较高剂量最终会抑制多巴胺神经元。在行为相关剂量下，巴氯芬激活两种细胞类型中的 GIRK 通道，但滥用药物 γ-羟基丁酸 (GHB) 仅激活 GABA 能神经元中的 GIRK 通道。因此，GABA(B) 受体激动剂由于 GIRK 亚基的细胞特异性表达而发挥平行的细胞和行为效应。
The rewarding effect of drugs of abuse is mediated by activation of the mesolimbic dopamine system, which is inhibited by putative anti-craving compounds. Interestingly, different GABA(B) receptor agonists can exert similarly opposing effects on the reward pathway, but the cellular mechanisms involved are unknown. Here we found that the coupling efficacy (EC50) of G-protein-gated inwardly rectifying potassium (GIRK, Kir3) channels to GABA(B) receptor was much lower in dopamine neurons than in GABA neurons of the ventral tegmental area (VTA), depending on the differential expression of GIRK subunits. Consequently, in rodent VTA slices, a low concentration of the canonical agonist baclofen caused increased activity, whereas higher doses eventually inhibited dopamine neurons. At behaviorally relevant dosages, baclofen activated GIRK channels in both cell types, but the drug of abuse gamma-hydroxy-butyric acid (GHB) activated GIRK channels only in GABAergic neurons. Thus GABA(B) receptor agonists exert parallel cellular and behavioral effects due to the cell- specific expression of GIRK subunits.