The Effects of Differential Rearing on Glutamate Homeostasis and Addiction

描述（由申请方提供）：与在标准（SC）或隔离条件（IC）下饲养的啮齿动物相比，在儿童期和青春期在富集条件（EC）下饲养的啮齿动物具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，包括对各种滥用药物的反应。这是公认的，饲养在EC降低的动机，以响应低剂量的精神兴奋剂相比，在IC提出的大鼠，然而，这种影响的神经生物学机制尚不清楚。一些研究已经观察到EC和IC大鼠之间的中皮质边缘通路中多巴胺能功能的差异。中皮质边缘通路的谷氨酸能传入介导对精神兴奋剂的反应，谷氨酸稳态的缺陷被假设为有助于药物成瘾。差异饲养改变谷氨酸能功能，因此本申请的首要假设是差异饲养改变谷氨酸稳态。据预测，富集增强谷氨酸稳态，这种增强有助于富集的能力，以防止药物滥用。相反，孤立损害谷氨酸稳态，这种损害有助于增加药物滥用的脆弱性。具体目标1将确定差异饲养是否改变谷氨酸稳态关键的受体和转运蛋白的功能。将检查mGluR 2/3、mGluR 5和GLT 1的激动剂和拮抗剂对差异饲养大鼠中苯丙胺自我给药的影响。具体目标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。在差异饲养大鼠中，在急性和重复安非他明后，将测量mGluR 2/3、mGluR 5和GLT 1在中皮质边缘多巴胺通路中的表达。支持这一假设的结果将表明，环境条件改变了多巴胺能功能，这些变化影响药物使用行为。在本申请中使用差异饲养模型将使得未来能够在显示环境诱导的连续奖励敏感性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。完成拟议的实验将加强堪萨斯州立大学心理学系的研究环境，并使学生能够参与探索差异饲养对谷氨酸稳态影响的研究计划的各个阶段。

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.