Role of DARPP-32: Individual Responsiveness to Nicotine

描述（由申请人提供）：烟草使用是世界上可预防的头号死亡原因。尼古丁（NIC）是烟草中含量最多的生物碱，是吸烟的主要补强剂。导致NIC易感性的因素有很多。其中一个因素就是环境。环境动物模型是在三种不同的条件之一中饲养大鼠：包含新物体和社会伙伴的丰富条件（EC），只包含社会伙伴的社会条件（SC），或者没有物体或伙伴的贫困条件（IC）。该动物模型确定了可能改变个体对药物滥用脆弱性的环境影响。环境刺激引起的对精神兴奋剂的行为反应的改变是通过多巴胺能神经传递的差异调节介导的。多巴胺(DA)/D1受体/cAMP/蛋白激酶A （PKA）调控信号通路的激活导致DA和cAMP调控的磷酸化蛋白-32 （DARPP-32）的磷酸化。众所周知，这种突触后信号通路对于反复暴露于滥用药物的细胞可塑性至关重要（Greengard等人，1999）。尽管有证据表明，对NIC成瘾的易感性存在个体差异，但对于环境富集对DARPP-32磷酸化的分子影响，以及与环境贫困大鼠相比，DARPP-32分子变化与NIC行为反应之间的潜在关系，我们知之甚少。该提案将验证环境富集改变DA受体介导的cAMP/PKA信号传导的总体假设，进而改变NIC对DARPP-32的影响，这些变化将有助于在EC和IC之间观察到NIC诱导的行为致敏的差异。该假设驱动该资助试图阐明环境影响NIC成瘾的潜在神经生物学机制。本实验主要有两个目的：1)确定反复注射NIC对EC、SC或IC大鼠的行为致敏性；2)确定环境富集介导的DARPP-32磷酸化变化与反复注射NIC对EC、SC或IC大鼠的行为致敏性之间的相关性。了解环境富集改变DA信号传导的机制将有可能促进烟草依赖治疗方案的发展，并有助于成年期预防和治疗干预策略的有效性。这些结果将阐明环境影响尼古丁成瘾的潜在神经生物学机制。了解这一机制将有可能促进烟草依赖治疗方案的发展，并将有助于成年期预防和治疗干预策略的有效性。

DESCRIPTION (provided by applicant): Tobacco use is the number one preventable cause of death in the world. Nicotine (NIC), the most abundant alkaloid in tobacco, is the primary reinforcing agent in tobacco smoking. Many factors contribute to susceptibility to NIC. One such factor is the environment. The environment animal model is that rats are raised in one of three different conditions: an enriched condition (EC) containing novel objects and social partners, a social condition (SC) containing social partners only, or an impoverished condition (IC) without objects or partners. This animal model identifies environmental influences that may alter individual vulnerability to drug abuse. Environmental stimuli-induced alterations in the behavioral response to psychostimulants are mediated through differential modulation of dopaminergic neurotransmission. Activation of the dopamine (DA)/D1 receptor/cAMP/protein kinase A (PKA)-regulated signaling pathway leads to phosphorylation of the DA and cAMP-regulated phosphoprotein-32 (DARPP-32). This postsynaptic signaling pathway is known to be essential for cellular plasticity in response to repeated exposures to drugs of abuse (Greengard et al., 1999). Although evidence shows individual differences in the susceptibility to NIC addiction, little is known about the molecular consequences of environmental enrichment on DARPP-32 phosphorylation, and the potential relationship between these molecular changes in DARPP-32 and behavioral responses to NIC compared to environmentally impoverished rats. This proposal will test overall hypothesis that environmental enrichment changes DA receptor-mediated cAMP/PKA signaling, in turn modifying the effects of NIC on DARPP-32, and these changes will contribute to differences in NIC-induced behavioral sensitization observed between EC and IC. The hypothesis that drives this grant attempts to elucidate the underlying neurobiological mechanisms of the environmental influences on NIC addiction. The experiments proposed here are designed to focus on two specific aims: 1) To determine the NIC-induced behavioral sensitization in EC, SC or IC rats following repeated NIC injection, 2) To determine the correlation between environmental enrichment-mediated changes in DARPP-32 phosphorylation and behavioral sensitization following repeated NIC injection in EC, SC or IC rats. An understanding of mechanisms by which environmental enrichment alters DA signaling will have the potential to facilitate the development of therapeutic programs for tobacco dependence, and will contribute to the effectiveness of prevention and treatment intervention strategies in adulthood. These results will elucidate the underlying neurobiological mechanisms of the environmental influences on nicotine addiction. Understanding this mechanism will have the potential to facilitate the development of therapeutic programs for tobacco dependence, and will contribute to the effectiveness of prevention and treatment intervention strategies in adulthood.