The Effects of Differential Rearing on Glutamate Homeostasis and Addiction

描述（由申请人提供）：与在标准（SC）或隔离条件（IC）中饲养的啮齿动物相比，在儿童和青少年时期在强化条件（EC）中饲养的啮齿动物具有各种神经生物学和行为差异。这些神经生物学上的差异影响着许多行为，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中饲养的大鼠对低剂量精神兴奋剂的反应动机降低，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大鼠中脑皮质边缘通路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，假设谷氨酸体内平衡的缺陷有助于药物成瘾。差异饲养改变谷氨酸功能，因此当前应用的总体假设是差异饲养改变谷氨酸稳态。据预测，富集增强了谷氨酸的内稳态，这种增强有助于富集防止药物滥用的能力。相反，分离会损害谷氨酸的体内平衡，这种损害会增加对药物滥用的脆弱性。特异性目的1将确定不同饲养方式是否会改变谷氨酸稳态关键受体和转运体的功能。mGluR2/3、mGluR5和glt1的激动剂和拮抗剂对不同饲养大鼠安非他明自我给药的影响将被检验。特异性目的2将检验不同饲养方式是否会改变维持谷氨酸稳态的蛋白质的表达。mGluR2/3、mGluR5和GLT1在中脑皮质边缘多巴胺通路的表达将在不同饲养的大鼠急性和反复服用安非他明后进行测量。支持这一假设的结果表明，环境条件会改变谷氨酸能功能，而这些变化会影响药物使用行为。在当前的应用中使用差异饲养模型将使未来的谷氨酸稳态理论在一个模型中得到验证，扩展和应用谷氨酸稳态理论，该模型显示了环境诱导的奖励敏感性连续体。这些实验将由本科生和研究生进行。实验的完成将加强堪萨斯州立大学心理学系的研究环境，并使学生能够参与研究项目的各个阶段，探索不同养育方式对谷氨酸稳态的影响。

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.