CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects
CREB activity in dopamine D1 receptor expressing neurons regulates cocaine-induced behavioral effects
复制标题
DOI：
10.3389/fnbeh.2014.00212
复制
发表时间：
2014-06-11
影响因子：
3
通讯作者：
Parkitna, Jan R.
中科院分区：
文献类型：
--
作者：
Bilbao, Ainhoa;Rieker, Claus;Parkitna, Jan R.
提示纹状体cAMP反应元件结合蛋白(CREB)调节对精神刺激剂的敏感性。为了检验这一假设的细胞特异性，我们检测了在多巴胺受体D1(D1R)神经元中表达的显性负CREB蛋白变体对可卡因诱导行为的影响。在D1R基因启动子的控制下，将含有A-CREB序列的BAC转基因原核注射获得转基因小鼠品系。与野生型相比，药物诱导的突变体在基因表达上表现出适度的变化，特别是活性调节转录本的基础水平降低，如Arc和Egr2。突变小鼠对可卡因的行为反应增强。与野生型相比，急性处理后的运动活动、间歇注射药物后的精神运动敏感化和生理盐水处理后的条件性运动增加。转基因小鼠有显著更高的可卡因条件性位置偏好，表现出正常的条件偏好消退，但在启动诱导恢复后表现出增强的可卡因寻找反应。这种增强的可卡因寻找反应与活性调节转录本和前强啡肽水平的增加有关。在突变小鼠中，可卡因的主要增强作用没有改变，因为它们在训练剂量下的固定比例计划下的可卡因自我给药方面与野生型没有不同。总之，我们的数据表明，显性-负性CREB变体仅在表达D1R的神经元中表达足以概括先前报道的与病毒表达的显性-负性CREB相关的行为表型。
It is suggested that striatal cAMP responsive element binding protein (CREB) regulates sensitivity to psychostimulants. To test the cell-specificity of this hypothesis we examined the effects of a dominant-negative CREB protein variant expressed in dopamine receptor D1 (D1R) neurons on cocaine-induced behaviors. A transgenic mouse strain was generated by pronuclear injection of a BAC-derived transgene harboring the A-CREB sequence under the control of the D1R gene promoter. Compared to wild-type, drug-naive mutants showed moderate alterations in gene expression, especially a reduction in basal levels of activity-regulated transcripts such as Arc and Egr2. The behavioral responses to cocaine were elevated in mutant mice. Locomotor activity after acute treatment, psychomotor sensitization after intermittent drug injections and the conditioned locomotion after saline treatment were increased compared to wild-type littermates. Transgenic mice had significantly higher cocaine conditioned place preference, displayed normal extinction of the conditioned preference, but showed an augmented cocaine-seeking response following priming-induced reinstatement. This enhanced cocaine-seeking response was associated with increased levels of activity-regulated transcripts and prodynorphin. The primary reinforcing effects of cocaine were not altered in the mutant mice as they did not differ from wild-type in cocaine self-administration under a fixed ratio schedule at the training dose. Collectively, our data indicate that expression of a dominant-negative CREB variant exclusively in neurons expressing D1 R is sufficient to recapitulate the previously reported behavioral phenotypes associated with virally expressed dominant-negative CREB.