Molecular Mechanisms of Environmental Enrichment

描述（由申请人提供）：药物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发展出强烈的渴望和强迫性药物使用典型的成瘾。因此，识别使人对成瘾具有抵抗力的因素不仅可用于治疗，而且可用于预防成瘾。目前的建议利用环境富集范例，非药物，非手术操作产生成瘾性表型的静脉药物自我管理的大鼠。具体而言，大鼠饲养在一个丰富的条件（EC），组住在大笼子里的新的儿童玩具，自我管理较少的可卡因或安非他明比大鼠提出了一个隔离的条件（IC）。重要的是，兴奋剂自我给药的减少是自我给药特有的，而不是由于一般性快感缺乏。我们的初步数据提供了很好的证据表明，保护性成瘾表型是由于，至少部分是由于转录因子cAMP反应元件结合蛋白（CREB）的活性降低，与减少神经元兴奋性的净效应的中缝核（NAc）多刺神经元。目前的建议的目的是进一步研究神经元兴奋性，因为它涉及到成瘾行为，并确定特定的机制，介导的EC和IC大鼠的NAC兴奋性。目的1将调查是否降低NAc的神经元兴奋性可以降低IC大鼠可卡因自我给药的倾向，并调查兴奋性降低是否会增加保护性EC表型。接下来，目标2将检查阳离子通道的mRNA表达作为介导保护性EC表型的可能的近端机制。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大鼠降低，以及兴奋性离子通道组的协调下调。最终的目的是确认目标2所确定的mRNA调控，然后研究EC、IC和SC大鼠中这些靶点的蛋白表达。这些实验的结果将揭示介导成瘾抗性的新基因靶点。此外，这些实验将确定NAc中CREB活性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，以加速理解环境在介导对成瘾的抵抗中的作用。

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.