Valverde Olga, Mantamadiotis Theo, Torrecilla María, Ugedo Luisa, Pineda Joseba, Bleckmann Susanne, Gass Peter, Kretz Oliver, Mitchell Jennifer M, Schütz Günther, Maldonado Rafael
Laboratori de Neurofarmacologia, Facultat de Ciènces de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.
Neuropsychopharmacology. 2004 Jun;29(6):1122-33. doi: 10.1038/sj.npp.1300416.
The transcription factor cAMP-responsive element binding protein (CREB) has been shown to regulate different physiological responses including drug addiction and emotional behavior. Molecular changes including adaptive modifications of the transcription factor CREB are produced during drug dependence in many regions of the brain, including the locus coeruleus (LC), but the molecular mechanisms involving CREB within these regions have remained controversial. To further investigate the involvement of CREB in emotional behavior, drug reward and opioid physical dependence, we used two independently generated CREB-deficient mice. We employed the Cre/loxP system to generate mice with a conditional CREB mutation restricted to the nervous system, where all CREB isoforms are lacking in the brain (Crebl(NesCre)). A genetically defined cohort of the previously described hypomorphic Crebl(alphadelta) mice, in which the two major transcriptionally active isoforms (alpha and delta) are disrupted throughout the organism, were also used. First, we investigated the responses to stress of the CREB-deficient mice in several paradigms, and we found an increased anxiogenic-like response in the both Creb1 mutant mice in different behavioral models. We investigated the rewarding properties of drugs of abuse (cocaine and morphine) and natural reward (food) using the conditioned place-preference paradigm. No modification of motivational responses of morphine, cocaine, or food was observed in mutant mice. Finally, we evaluated opioid dependence by measuring the behavioral expression of morphine withdrawal and electrophysiological recordings of LC neurons. We showed an important attenuation of the behavioral expression of abstinence and a decrease in the hyperactivity of LC neurons in both Creb1 mutant mice. Our results emphasize the selective role played by neuronal CREB in emotional-like behavior and the somatic expression morphine withdrawal, without participating in the rewarding properties induced by morphine and cocaine.
转录因子环磷酸腺苷反应元件结合蛋白（CREB）已被证明可调节包括药物成瘾和情绪行为在内的不同生理反应。在药物依赖过程中，包括蓝斑（LC）在内的大脑许多区域会产生包括转录因子CREB适应性修饰在内的分子变化，但这些区域内涉及CREB的分子机制仍存在争议。为了进一步研究CREB在情绪行为、药物奖赏和阿片类物质身体依赖中的作用，我们使用了两种独立产生的CREB缺陷小鼠。我们采用Cre/loxP系统来生成条件性CREB突变仅限于神经系统的小鼠，其大脑中所有CREB亚型均缺失（Crebl(NesCre)）。我们还使用了先前描述的低表达Crebl(alphadelta)小鼠的一个基因定义群体，其中两种主要的转录活性亚型（α和δ）在整个生物体中均被破坏。首先，我们在几种范式中研究了CREB缺陷小鼠对应激的反应，发现在不同行为模型中，两种Creb1突变小鼠的焦虑样反应均增加。我们使用条件性位置偏好范式研究了滥用药物（可卡因和吗啡）和自然奖赏（食物）的奖赏特性。在突变小鼠中未观察到吗啡、可卡因或食物的动机反应有改变。最后，我们通过测量吗啡戒断的行为表现和LC神经元的电生理记录来评估阿片类物质依赖。我们发现两种Creb1突变小鼠的戒断行为表现均有显著减弱，且LC神经元的多动性降低。我们的结果强调了神经元CREB在情绪样行为和吗啡戒断的躯体表现中所起的选择性作用，而不参与吗啡和可卡因诱导的奖赏特性。
