The Effects of Differential Rearing on Glutamate Homeostasis and Addiction

描述(申请人提供)：与在标准(SC)或隔离(IC)条件下饲养的啮齿动物相比，在儿童和青春期在丰富条件(EC)中饲养的啮齿动物有各种神经生物学和行为差异。这些神经生物学差异影响了许多行为，包括对各种药物滥用的反应。众所周知，与在IC中饲养的大鼠相比，在EC中饲养会降低对低剂量精神刺激剂的反应动机，然而，这种效应的神经生物学机制尚不清楚。一些研究已经观察到EC和IC大鼠在中皮质边缘通路中的多巴胺能功能的差异。谷氨酸能传入中皮质边缘通路，介导对精神刺激剂的反应，谷氨酸稳态缺陷被认为与药物成瘾有关。不同的饲养方式改变了谷氨酸能功能，因此，目前应用的主要假说是，不同的饲养方式改变了谷氨酸的稳态。据预测，浓缩增强了谷氨酸的动态平衡，这种增强有助于浓缩以防止药物滥用。相反，隔离会损害谷氨酸稳态，这种损害会增加药物滥用的易感性。具体目标1将确定差异饲养是否会改变对谷氨酸稳态至关重要的受体和转运体的功能。将检测mGluR2/3、mGluR5和GLT1的激动剂和拮抗剂对不同饲养大鼠苯丙胺自我给药的影响。特定目标2将检查差异饲养是否改变了有助于维持谷氨酸稳态的蛋白质的表达。在不同饲养的大鼠中，将检测急性和重复安非他明后mGluR2/3、mGluR5和GLT1在皮质边缘多巴胺通路中的表达。支持这一假说的结果将表明，环境条件改变了谷氨酸能功能，这些改变影响了药物使用行为。在目前的应用中使用差异饲养模型将使未来能够在显示环境诱导的奖励敏感性连续体的模型中测试谷氨酸稳态理论，以验证、扩展和应用谷氨酸稳态理论。这些实验将由本科生和研究生进行。拟议中的实验的完成将加强堪萨斯州立大学心理学系的研究环境，并将使学生能够参与探索差异饲养对谷氨酸稳态的影响的研究计划的所有阶段。

DESCRIPTION (provided by applicant): Rodents reared in enriched conditions (EC) during childhood and adolescence have a variety of neurobiological and behavioral differences when compared to rodents reared in standard (SC) or isolated conditions (IC). These neurobiological differences impact numerous behaviors, including the response to a variety of drugs of abuse. It is well established that rearing in an EC reduces the motivation to respond for low doses of psychostimulants when compared to rats raised in an IC, however, the neurobiological mechanism for this effect remains unclear. Several studies have observed differences in dopaminergic function in the mesocorticolimbic pathway between EC and IC rats. Glutamatergic afferents to the mesocorticolimbic pathway mediate the response to psychostimulants and deficits in glutamate homeostasis are hypothesized to contribute to drug addiction. Differential rearing alters glutamatergic function and therefore the overarching hypothesis of the current application is that differential rearing alters glutamate homeostasis. It is predicted that enrichment augments glutamate homeostasis and this augmentation contributes to the ability of enrichment to protect against drug abuse. Conversely, isolation impairs glutamate homeostasis and this impairment contributes to the increased vulnerability to drug abuse. Specific Aim 1 will determine if differential rearing alters the function of receptors and transporters critical for glutamate homeostasis. The effect of agonists and antagonists to mGluR2/3, mGluR5, and GLT1on the self-administration of amphetamine in differentially reared rats will be examined. Specific Aim 2 will examine if differential rearing alters the expression of proteins that contribue to the maintenance of glutamate homeostasis. The expression of mGluR2/3, mGluR5, and GLT1 in the mesocorticolimbic dopamine pathway will be measured following acute and repeated amphetamine in differentially reared rats. Results supporting this hypothesis will suggest that environmental conditions alter glutamatergic function and that these changes affect drug use behavior. Use of the differential rearing model in the current application will enable future testing of the glutamate homeostasis theory in a model that displays an environmentally-induced continuum of reward sensitivity to validate, expand, and apply the glutamate homeostasis theory. These experiments will be conducted by undergraduate and graduate students. Completion of the proposed experiments will strengthen the research environment in the Kansas State University Psychology Department and will enable students to participate in all phases of a research program exploring the effects of differential rearing on glutamate homeostasis.