Role of DARPP-32: Individual Responsiveness to Nicotine

描述（由申请人提供）：烟草使用是世界上头号可预防的死亡原因。尼古丁（NIC）是烟草中含量最丰富的生物碱，是烟草吸味的主要增强剂.许多因素导致对NIC的易感性。其中一个因素是环境。环境动物模型是将大鼠饲养在三种不同条件之一中：包含新对象和社会伙伴的丰富条件（EC）、仅包含社会伙伴的社会条件（SC）或没有对象或伙伴的贫困条件（IC）。该动物模型确定了可能改变个体对药物滥用的脆弱性的环境影响。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）调节的信号通路的激活导致DA和cAMP调节的磷蛋白-32（DARPP-32）的磷酸化。已知这种突触后信号传导途径对于响应于重复暴露于滥用药物的细胞可塑性是必不可少的（Greengard等人，1999年）。尽管有证据表明NIC成瘾易感性的个体差异，但环境富集对DARPP-32磷酸化的分子后果以及DARPP-32中这些分子变化与NIC行为反应之间的潜在关系与环境贫困大鼠相比知之甚少。该提案将检验以下总体假设：环境富集改变DA受体介导的cAMP/PKA信号传导，进而改变NIC对DARPP-32的影响，并且这些变化将有助于在EC和IC之间观察到的NIC诱导的行为敏化的差异。推动这项资助的假设试图阐明环境对NIC成瘾影响的潜在神经生物学机制。本文提出的实验旨在关注两个具体目的：1）确定重复NIC注射后EC、SC或IC大鼠中NIC诱导的行为敏化，2）确定EC、SC或IC大鼠中重复NIC注射后环境富集介导的DARPP-32磷酸化变化与行为敏化之间的相关性。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，并将有助于成年期预防和治疗干预策略的有效性。这些结果将阐明尼古丁成瘾的环境影响的神经生物学机制。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.