Paradoxical effects of prodynorphin gene deletion on basal and cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens
Paradoxical effects of prodynorphin gene deletion on basal and cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens
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DOI：
10.1111/j.1460-9568.2005.04525.x
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发表时间：
2006-01-01
影响因子：
3.4
通讯作者：
Shippenberg, TS
中科院分区：
文献类型：
--
作者：
Chefer, VI;Shippenberg, TS
定量和常规的微透析被用来调查的组成性缺失的前强啡肽基因的基础多巴胺（DA）的动力学在延髓核（NAc）和DA神经元的反应性的影响，以急性可卡因的挑战。还评估了盐水和可卡因诱发的自发活动。定量微透析显示，基础细胞外DA水平下降，而DA提取分数，DA摄取的间接措施，在强啡肽（DYN）敲除（KO）小鼠不变。可卡因增加NAc DA水平的能力在KO中降低。同样，可卡因诱发的运动活动减少KO。选择性κ阿片受体激动剂U-69593降低野生型小鼠NAc透析液DA水平，这种作用在KO中增强。给KO小鼠施用选择性κ阿片受体（KOPr）拮抗剂nor-binaltorphimine可减弱可卡因诱导的DA水平降低。然而，它是无效的，在改变减少运动反应可卡因。这些研究表明，组成性缺失的前强啡肽与细胞外NAc DA水平的降低和急性可卡因的反应性降低。关于U-69593和nor-binaltorphimine在KO中的作用的数据表明，由于强啡肽原基因缺失，κ阿片受体上调，并且这种适应是在DYN KO小鼠中观察到的基础DA动力学和可卡因诱发的DA水平降低的基础。这些发现表明，DYN KO小鼠的表型不仅是由于内源性阿片肽的损失，而且还反映了在阿片受体水平发生的发育补偿。
Quantitative and conventional microdialysis were used to investigate the effects of constitutive deletion of the prodynorphin gene on basal dopamine (DA) dynamics in the nucleus accumbens (NAc) and the responsiveness of DA neurons to an acute cocaine challenge. Saline- and cocaine-evoked locomotor activity were also assessed. Quantitative microdialysis revealed that basal extracellular DA levels were decreased, while the DA extraction fraction, an indirect measure of DA uptake, was unchanged in dynorphin (DYN) knockout (KO) mice. The ability of cocaine to increase NAc DA levels was reduced in KO. Similarly, cocaine-evoked locomotor activity was decreased in KO. The selective kappa opioid receptor agonist U-69593 decreased NAc dialysate DA levels in wildtype mice and this effect was enhanced in KO. Administration of the selective kappa opioid receptor (KOPr) antagonist nor-binaltorphimine to KO mice attenuated the decrease in cocaine-induced DA levels. However, it was ineffective in altering the decreased locomotor response to cocaine. These studies demonstrate that constitutive deletion of prodynorphin is associated with a reduction of extracellular NAc DA levels and a decreased responsiveness to acute cocaine. Data regarding the effects of U-69593 and nor-binaltorphimine in KO suggest that the kappa opioid receptor is up-regulated as a consequence of prodynorphin gene deletion and that this adaptation underlies the decrease in basal DA dynamics and cocaine-evoked DA levels observed in DYN KO mice. These findings suggest that the phenotype of DYN KO mice is not solely due to loss of endogenous opioid peptide but also reflects developmental compensations that occur at the level of the opioid receptor.