The Effects of Differential Rearing on Glutamate Homeostasis and Addiction

差异饲养对谷氨酸稳态和成瘾的影响

基本信息

批准号：
8497083
负责人：
Mary Eileen Cain
金额：
$ 43.63万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8497083
关键词：
Acute Adolescence Affect Agonist Amphetamines Area Behavior Behavioral Brain Childhood Dopamine Dose Drug Addiction Drug abuse Drug usage Environment Environmental Risk Factor Functional disorder Future Glutamates Homeostasis Impairment Intravenous Kansas Maintenance Measures Medial Mediating Modeling Motivation Neurobiology Neurons Nucleus Accumbens Pathway interactions Phase Predisposition Prefrontal Cortex Psychology Rattus Regulation Research Rewards Rodent Role Self Administration Students Sucrose Synapses System Testing Universities addiction drug of abuse emerging adult graduate student metabotropic glutamate receptor 2 neurobiological mechanism neuromechanism non-drug pre-clinical programs protein expression psychostimulant public health relevance receptor receptor function reinforcer research study response theories undergraduate student

项目摘要

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.

描述（由申请人提供）：与在标准（SC）或孤立条件（IC）中饲养的啮齿动物相比，儿童期和青春期期间在富含条件（EC）的啮齿动物具有多种神经生物学和行为差异。这些神经生物学差异会影响许多行为，包括对各种滥用药物的反应。可以很好地确定，与在IC中饲养的大鼠相比，在EC中饲养可以减少低剂量的心理刺激物的动机，但是，这种效果的神经生物学机制尚不清楚。几项研究观察到在EC和IC大鼠之间的中质体途径中多巴胺能功能的差异。假设谷氨酸能传入的中皮质核途径介导对精神刺激剂的反应和谷氨酸稳态的缺陷，以便有助于吸毒。差异饲养会改变谷氨酸能的功能，因此当前应用的总体假设是差异饲养会改变谷氨酸稳态。据预测，富集增强了谷氨酸稳态，这种增强有助于富集防止药物滥用。相反，隔离会损害谷氨酸稳态，而这种损害有助于增加对药物滥用的脆弱性。特定的目标1将确定差异饲养是否会改变受体和转运蛋白对谷氨酸稳态至关重要的功能。激动剂和拮抗剂对MGLUR2/3，MGLUR5和GLT1ON的影响将检查二型大鼠中苯丙胺的自给剂。特定目标2将检查差异饲养是否会改变有助于维持谷氨酸稳态的蛋白质的表达。在差异饲养的大鼠中急性和重复的苯丙胺后，将测量中皮质糖多巴胺途径中MGLUR2/3，MGLUR5和GLT1的表达。支持该假设的结果将表明环境条件改变了谷氨酸能功能，这些变化会影响药物使用行为。在当前应用中使用差异饲养模型将在一个模型中对谷氨酸稳态理论进行未来的测试，该模型显示出环境诱导的奖励灵敏度连续性，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，并使学生能够参与研究计划的所有阶段，探讨差异饲养对谷氨酸稳态的影响。