INTRACELLULAR MOLECULES OF NICOTINE ADDICTION

描述（改编自申请人摘要）： 药物成瘾的分子基础最近已经被探索， 基因敲除小鼠这些研究揭示了一些分子 有助于成瘾的不同方面的兴奋剂，阿片类药物， 乙醇然而，尼古丁成瘾的分子基础仍不清楚 尽管对尼古丁和其他药物的成瘾有着共同的 神经解剖学基础转录因子FosB和蛋白质 磷酸酶抑制剂DARPP-32（多巴胺和cAMP调节的磷酸蛋白， 32 kDa）已被证明是不同方面的关键决定因素， 对可卡因的行为反应这两种细胞内分子 是独一无二的，因为它们的破坏使动物更容易受到可卡因的影响， 行为效应本申请被设计为测试该假设 这两种分子对尼古丁成瘾也至关重要，如果 因此，它们在尼古丁依赖的特定方面发挥着不同的作用。 实验设计在三个方面有独到之处。首先，一些 行为模型将用于评估尼古丁的不同方面， 成瘾它们包括容忍、敏感、条件性位置偏好， 戒断相关的条件性位置厌恶和自我管理。 其次，将尝试评估遗传背景的影响 行为表型基因敲除和基因敲除的遗传背景不同， 野生型小鼠同窝仔混淆了行为表型， 基因敲除小鼠杂合小鼠将与C57 BL/6 J重复回交 小鼠的遗传背景达到更高程度的相似性， 敲除小鼠和野生型同窝出生小鼠（即，同类小鼠）。第三、 解剖学分析将确定神经解剖学的参与 行为表型的适应。根据类似的结果， 可卡因成瘾的方法，预计这两个基因有助于 尼古丁成瘾的具体方面。如果这些分子被证明是 对于尼古丁成瘾的脆弱性很重要，这项小鼠研究将 为人类成瘾脆弱性的遗传分析提供了坚实的基础。

DESCRIPTION(Adapted from applicant's abstract): The molecular basis of drug addiction has recently been explored using knock-out mice. These studies have revealed that a number of molecules contribute to distinct aspects of addiction to stimulants, opiates, and ethanol. However, the molecular basis of nicotine addiction remains unclear despite the fact that addiction to nicotine and other drugs shares a common neuroanatomical basis. The transcription factor FosB and the protein phosphatase inhibitor DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) have been shown to be critical determinants for different aspects of behavioral responsiveness to cocaine in mice. These two intracellular molecules are unique in that their disruption makes animals more vulnerable to cocaine's behavioral effects. The present application is designed to test the hypothesis that these two molecules are also critical for nicotine addiction and that, if so, they play distinct roles in specific aspects of nicotine dependence. The experimental design is unique in three aspects. First, a number of behavioral models will be used to assess different aspects of nicotine addiction. They include tolerance, sensitization, conditioned place preference, withdrawal-associated conditioned place aversion, and self-administration. Second, an attempt will be made to assess the influence of genetic backgrounds on behavioral phenotypes. The dissimilar genetic backgrounds of knock-out and wild-type mice littermates have confounded the behavioral phenotypes of knock-out mice. Heterozygous mice will be repeatedly back-crossed to C57BL/6J mice to achieve a higher degree of similarity in the genetic backgrounds of knock-out mice and wild-type littermates (i.e., congenic mice). Third, anatomical analysis will determine the involvement of neuroanatomical adaptations in behavioral phenotypes. Based on the outcome of similar approaches to cocaine addiction, it is expected that these two genes contribute to specific aspects of nicotine addiction. If these molecules turn out to be important for vulnerability to nicotine addiction, this mouse study will provide a solid basis for genetic analysis of human addiction vulnerability.