Antisense-induced reduction in nucleaus accumbens cyclic AMP response element binding protein attenuates cocaine reinforcement
Antisense-induced reduction in nucleaus accumbens cyclic AMP response element binding protein attenuates cocaine reinforcement
复制标题
DOI：
10.1016/j.neuroscience.2005.10.049
复制
发表时间：
2006-01-01
期刊：
影响因子：
3.3
通讯作者：
Self, DW
中科院分区：
文献类型：
--
作者：
Choi, KH;Whisler, K;Self, DW
重复可卡因暴露上调环AMP信号传导，并增加环AMP反应元件结合蛋白（CREB）的转录活性在丘脑核。为了研究髓核CREB活性调节自我给药行为的可能性，我们测试了单次双侧向髓核核心和壳亚区输注CREB反义寡核苷酸对大鼠可卡因自我给药的影响。CREB反义核芯注入减少CREB和CREB调节的立即早期基因脑源性神经营养因子分别为31%和27%，但未能改变同源CREB家族蛋白质环AMP反应元件调节剂和激活转录因子1的水平，并且对邻近核壳组织中的CREB水平没有影响。在核心或外壳中类似地输注CREB反义物在固定比率5（5个响应/注射）强化时间表上产生可卡因自我施用剂量-响应曲线的短暂下移，表明可卡因强化减少，其在治疗后3天完全恢复。CREB反义还增加了恢复可卡因自我给药所需的可卡因阈值剂量，表明核内CREB水平调节可卡因的刺激特性。当获得可卡因在固定比率1时间表上限制较少时，在核心而不是外壳中输注CREB反义引起稳定的可卡因自我给药的短暂（1-2天）减少，但对由蔗糖颗粒维持的响应没有影响，这表明核内的基础CREB水平调节药物摄入。这些影响都没有产生的互补正义寡核苷酸注入核内。这些结果表明，在可卡因强化核CREB活性的必要作用，并通过匡威类比，慢性可卡因使用后CREB活性的上调可能有助于可卡因自我管理成瘾相关的增加。(c)2005由Elsevier Ltd代表IBRO出版。
Repeated cocaine exposure up-regulates cyclic AMP signaling and increases the transcriptional activity of cyclic AMP response element binding protein (CREB) in the nucleus accumbens. To study the possibility that nucleus accumbens CREB activity regulates self-administration behavior, we tested the effects of a single, bilateral infusion of CREB antisense oligonucleotide into nucleus accumbens core and shell sub-regions on cocaine self-administration in rats. Nucleus accumbens core infusions of CREB antisense reduced CREB and the CREB-regulated immediate early gene brain-derived neurotrophic factor by 31 and 27%, respectively, but failed to alter levels of the homologous CREB family proteins cyclic AMP response element modulator and activating transcription factor 1, and had no effect on CREB levels in adjacent nucleus accumbens shell tissue. Similar infusions of CREB antisense in either core or shell produced a transient downward shift in cocaine self-administration dose-response curves on a fixed ratio 5 (five responses/injection) reinforcement schedule, indicating a reduction in cocaine reinforcement that fully recovered 3 days after treatment. CREB antisense also increased the threshold dose of cocaine required for reinstating cocaine self-administration, indicating that nucleus accumbens CREB levels regulate the incentive properties of cocaine. When access to cocaine was less restricted on a fixed ratio 1 schedule, infusion of CREB antisense in the core, but not shell, caused a transient (1-2 days) reduction in stabilized cocaine self-administration, but had no effect on responding maintained by sucrose pellets, indicating that basal CREB levels in the nucleus accumbens core regulate drug intake. None of these effects were produced by nucleus accumbens infusions of complementary sense oligonucleotide. These results suggest a necessary role for nucleus accumbens CREB activity in cocaine reinforcement, and, by converse analogy, up-regulation in CREB activity after chronic cocaine use could contribute to addiction-related increases in cocaine self-administration. (c) 2005 Published by Elsevier Ltd on behalf of IBRO.