Molecular Mechanisms of Environmental Enrichment

描述（由申请人提供）：吸毒成瘾的一个奇怪的方面是，大多数尝试非法药物的人并没有产生强烈的渴望和强迫性吸毒成瘾的典型症状。因此，识别使一个人抵抗成瘾的因素不仅适用于治疗，也适用于预防成瘾。目前的建议利用环境富集范式，一种非药物、非手术操作，在大鼠静脉注射药物自我给药中产生抗成瘾表型。具体来说，在强化条件下（EC）饲养的老鼠，在有新奇儿童玩具的大笼子里饲养的老鼠，比在隔离条件下（IC）饲养的老鼠自我服用更少的可卡因或安非他明。重要的是，自我给药的减少是特定于自我给药的，而不是由于普遍的快感缺乏。我们的初步数据提供了很好的证据，证明保护性成瘾表型至少在一定程度上是由于转录因子cAMP反应元件结合蛋白（CREB）活性的降低，其净效应是伏核（NAc）中棘神经元的神经元兴奋性降低。本研究的目的是进一步研究神经元兴奋性与上瘾行为的关系，并确定EC和IC大鼠NAc兴奋性的具体机制。目的1将研究降低NAc神经元兴奋性是否能降低IC大鼠的可卡因自我给药倾向，并研究兴奋性降低是否会增加保护性EC表型。接下来，Aim 2将研究阳离子离子通道mRNA表达作为介导保护性EC表型的可能近端机制。例如，该研究将检查兴奋性离子通道的基础表达，假设EC大鼠NAc中特定离子通道的表达相对于IC大鼠减少，以及兴奋性离子通道组的协同下调。最终目的是确认aim 2鉴定的mRNA调控，然后研究这些靶点在EC、IC和SC大鼠中的蛋白表达。这些实验的结果将揭示新的基因靶点介导对成瘾的抵抗。此外，这些实验将确定NAc中CREB活动与成瘾相关行为之间的关键“缺失环节”。最后，这些实验将提供新的工具来加速理解环境在介导成瘾抵抗中的作用。

DESCRIPTION (provided by applicant): One curious aspect of drug addiction is that a majority of people experimenting with illicit drugs do not develop the intense craving and compulsive drug use typifying addiction. Thus, identifying factors rendering a person resistant to addiction has application not only for treatment, but also for prevention of addiction. The current proposal exploits the environmental enrichment paradigm, a non-drug, non-surgical manipulation producing an addiction-resistant phenotype for intravenous drug self-administration in rats. Specifically, rats reared in an enriched condition (EC), group housed in large cages with novel children's toys, self administer less cocaine or amphetamine than rats raised in an isolated condition (IC). Importantly, the decrease in stimulant self administration is specific to self administration and not due to general anhedonia. Our preliminary data offer good evidence that the protective addiction phenotype is due, at least in part, to decreases in activity of the transcription factor cAMP response-element binding protein (CREB), with the net effect of decreasing neuronal excitability of nucleus accumbens (NAc) medium spiny neurons. The purpose of the current proposal is to further investigate neuronal excitability as it relates to addictive behavior and identify specific mechanisms mediating NAc excitability in EC and IC rats. Aim 1 will investigate whether or not decreasing neuronal excitability in the NAc can reduce the propensity for cocaine self administration in IC rats, and also to investigate if decreased excitability will be additive to the protective EC phenotype. Next, Aim 2 will examine mRNA expression of cationic ion channels as possible proximal mechanisms mediating the protective EC phenotype. For example, the study will examine basal expression of excitatory ion channels, hypothesizing decreased expression of specific ion channels in NAc of EC rats relative to IC rats, and for coordinated downregulation of groups of excitatory ion channels. The final aim will confirm mRNA regulation identified by Aim 2 and then study protein expression of these targets in EC, IC and SC rats. The results of these experiments will uncover novel gene targets mediating resistance to addiction. Further, these experiments will identify the critical "missing links" between CREB activity in the NAc and addiction-relevant behavior. Lastly, these experiments will provide new tools to accelerate understanding of the role of environment in mediating resistance to addiction. PUBLIC HEALTH RELEVANCE: We know that environment plays a critical role in susceptibility to drug addiction, and rearing rats in an enriched environment renders them resistant to addiction-like behavior in models of intravenous self administration. This project will identify molecular mechanisms underlying the protective effect of environmental enrichment and strengthen our understanding of how gene transcription affects behavior. The results of this project will lay the foundation for future treatment and prevention of drug addiction in humans.