INTRACELLULAR MOLECULES OF NICOTINE ADDICTION

描述(改编自申请人的摘要)： 最近，药物成瘾的分子基础已经被用 基因敲除的老鼠。这些研究揭示了一些分子 导致对兴奋剂、鸦片类药物上瘾的不同方面 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上瘾有一个共同的 神经解剖学基础。转录因子FosB与蛋白质 磷酸酶抑制剂DARPP-32(多巴胺和cAMP调节的磷酸蛋白 32 kDa)被证明是不同方面的关键决定因素 小鼠对可卡因的行为反应。这两个细胞内分子 它们的独特之处在于它们的破坏使动物更容易受到可卡因的伤害 对行为的影响。本申请旨在检验这一假设 这两个分子对尼古丁成瘾也是至关重要的，如果 因此，它们在尼古丁依赖的特定方面扮演着不同的角色。 实验设计在三个方面独树一帜。首先，一些 行为模型将被用来评估尼古丁的不同方面 上瘾。它们包括耐受性、敏感化、条件性位置偏爱、 戒断相关的条件性位置厌恶和自我管理。 第二，将尝试评估遗传背景的影响 关于行为表型。基因敲除和基因缺失的不同遗传背景 野生型小鼠的窝产仔混淆了 基因敲除的老鼠。杂合子小鼠将反复回交到C57BL/6J 小鼠在遗传背景上达到更高的相似性 基因敲除小鼠和野生型小鼠(即同源小鼠)。第三, 解剖分析将确定神经解剖学的牵涉 行为表型的适应性。基于类似的结果 可卡因成瘾的途径，预计这两个基因起作用 尼古丁成瘾的特定方面。如果这些分子被证明是 对尼古丁成瘾的易感性很重要，这项小鼠研究将 为人类成瘾易感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.