Molecular Cognition of Addiction

描述（由申请人提供）：记忆和成瘾都会产生长期的行为变化，并导致对重复神经活动的慢性神经适应。因此，记忆和成瘾很可能在相同的神经结构中使用相同的突触可塑性分子机制。在目前的建议中，我们通过研究已知的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，我们可以快速量化对重复可卡因注射的精神运动致敏，以及对可卡因给药相关线索的条件反应，可卡因致敏表达的环境控制，以及可卡因诱导的条件位置偏好。首先，我们使用这一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，我们使用诱导和区域特异性破坏钙/钙调素依赖性蛋白激酶II (CaMKII)，这是成瘾中记忆形成的关键激酶。最后，我们研究了钙调蛋白在成瘾中的作用。使用现代基因操作的一个好处是能够通过破坏树突翻译和诱导区域特异性破坏前脑和纹状体中的α - camki来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，诱导后CaMKII或钙调蛋白的破坏，实际上有可能逆转对可卡因和相关记忆的致敏。综上所述，这些研究将评估记忆和成瘾相关的行为可塑性之间的相似之处，并为记忆的操纵是否在成瘾的治疗中被证明是有用的提供可观的启示。成瘾是影响数百万强迫性吸毒者的主要社会和医疗问题。在目前的建议中，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，那么记忆的破坏可能在成瘾的治疗中非常有用。

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.