Molecular Cognition of Addiction

描述(由申请人提供)：记忆和成瘾都会在行为上产生长期的变化，并导致慢性神经适应，以响应重复的神经活动。因此，记忆和成瘾很可能在相同的神经结构中招募了一些相同的突触可塑性分子机制。在目前的提案中，我们通过检查已知影响记忆的遗传和解剖操作对成瘾相关行为可塑性的影响来探索成瘾和记忆之间的相似之处。在一个简单的小鼠行为范式中，我们可以快速量化反复注射可卡因的精神运动敏感化，以及与可卡因注射相关的线索的条件性反应，对可卡因敏化表达的上下文控制，以及可卡因诱导的条件性位置偏爱。首先，我们使用这个范式来评估海马体和杏仁核在成瘾相关记忆中的作用。其次，我们在成瘾中使用了可诱导的和区域特异性的钙/钙调蛋白依赖蛋白激酶II(CaMKII)的干扰，CaMKII是记忆形成中的一种关键激酶。最后，我们研究了钙调素在成瘾中的作用。使用现代基因操作的一个好处是，通过干扰树突翻译和诱导前脑和纹状体中α-CaMKI的区域特异性干扰，能够更好地定位关键的神经适应。我们提出的可诱导和可逆的分子操作，即诱导后对CaMKII或钙调素的干扰，实际上有可能逆转对可卡因和相关记忆的敏化。综上所述，这些研究将评估记忆和与成瘾相关的行为可塑性之间的相似之处，并阐明记忆的操纵是否会被证明在治疗成瘾方面有用。项目叙事成瘾是影响数百万强迫症吸毒者的一个主要社会和医学问题。在目前的提案中，我们在大脑水平上研究记忆和成瘾之间的关系。如果记忆和成瘾被证明是高度相关的，那么记忆障碍可能会被证明在治疗成瘾方面非常有用。

DESCRIPTION (provided by applicant): Both memory and addiction produce long-lasting changes in behavior and result in chronic neural adaptations in response to repeated neural activity. It is therefore likely that memory and addiction recruit some of the same molecular mechanisms of synaptic plasticity in the same neural structures. In the present proposal, we explore the parallels between addiction and memory by examining the impact of genetic and anatomical manipulations known to affect memory on addiction-related behavioral plasticity. In a simple behavioral paradigm in mice we can rapidly quantify psychomotor sensitization to repeated cocaine injections, as well as the conditioned response to cues associated with cocaine administration, the contextual control over the expression of cocaine sensitization, and conditioned place preference induced by cocaine. First, we use this paradigm to evaluate the role of the hippocampus and amygdala in addiction-related memory. Second, we use inducible and region-specific disruption of calcium/calmodulin- dependent protein kinase II (CaMKII), a criticial kinase in memory formation, in addiction. Finally, we examine the role of calcium calmodulin in addiction. A benefit of using modern genetic manipulation is the ability to better localize key neuroadaptations through disruption of dendritic translation, and inducible region-specific disruption of alpha-CaMKI in the forebrain and striatum. The inducible and reversible molecular manipulations we propose, post-induction disruption of CaMKII or calcium calmodulin, actually have the potential to reverse sensitization to cocaine and related memories. Taken together, these studies will evaluate the parallels between memory and addiction-related behavioral plasticity and shed considerable light on whether manipulations of memory will prove useful in the treatment of addiction.Project Narrative Addiction is a major social and medical problem affecting millions of compulsive drug users. In the present proposal we examine the relationship between memory and addiction at the level of the brain. If memory and addiction prove to be highly related, disruptions of memory may prove highly useful in the treatment of addiction.