BIOCHEMICAL CORRELATES OF DRUG ABUSE VULNERABILITY

药物滥用脆弱性的生化相关性

• 批准号: 2120535
• 负责人: CHARLES W BRADBERRY
• 金额: $ 9.16万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-25 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2120535
• 关键词: G protein; amphetamines; behavior prediction; behavioral habituation /sensitization; biological models; chordate locomotion; corpus striatum; cyclic AMP; dopamine; dopamine receptor; drug addiction; frontal lobe /cortex; gamma aminobutyrate; laboratory rat; lenticular nucleus; microdialysis; model design /development; neurobiology; nucleus accumbens; postmortem; receptor binding; self stimulation; stress; synapses; G protein; amphetamines; behavior prediction; behavioral habituation /sensitization; biological models; chordate locomotion; corpus striatum; cyclic AMP; dopamine; dopamine receptor; drug addiction; frontal lobe /cortex; gamma aminobutyrate; laboratory rat; lenticular nucleus; microdialysis; model design /development; neurobiology; nucleus accumbens; postmortem; receptor binding; self stimulation; stress; synapses

In both the human clinical situation, and animal models of drug abuse, there are substantial differences between individuals in the amounts of drugs consumed. In an attempt to understand the neurobiology of drug abuse, and relapse following abstention, biochemical correlates of vulnerability to amphetamine self-administration in the rat will be studied. These studies will expand upon recent findings which demonstrate that certain behavioral measures (novelty-and amphetamine-induced locomotion) predict the amount of amphetamine self-administered by animals. Because of the role of the mesoaccumbens dopamine system in supporting both self-administration and amphetamine-induced locomotion, these studies will primarily focus on this system. This proposal is based on the hypothesis that the individual differences between animals which render some more vulnerable to drug self-administration are reflected in measurable biochemical differences. Measurable indices of both pre-and postsynaptic dopaminergic transmission in the nucleus accumbens will be examined. There are four basic aims of this proposal. The first will be to determine to what degree differences in presynaptic dopamine function correlate with differences in novelty-and amphetamine-induced locomotion. Specific experiments will examine amphetamine-induced dopamine release in vivo following local perfusion through a microdialysis probe: 2) amphetamine-induced dopamine release in vitro; 3) whole tissue measures of dopamine and metabolite under basal conditions; 4) dopamine uptake site density. The second specific aim examines mechanisms post-synaptic to dopaminergic actions in the nucleus accumbens for correlation with behavioral predictors: 1) dopamine receptor binding in the accumbens and striatum, 2) dopamine receptor mediated changes in cyclic AMP using accumbens and striatal tissue in vitro, and 3) gamma-aminobutyric acid receptor binding in the ventral pallidum. The third specific aim will determine the correlation between behavioral predictors and the following measures which attempt to determine the "degree of behavioral sensitization" in individual animals: 1) systemic amphetamine-induced dopamine release in vivo, measured by microdialysis in awake rats: 2) morphine-induced locomotion and dopamine release in vivo; 3) stress (novelty) induced increases in extracellular dopamine in the prefrontal cortex and nucleus accumbens. G-protein levels will be determined for correlation with novelty-induced locomotion, novelty-and amphetamine- induced increases in extracellular dopamine, and the effects of pertussis toxin treatment in the ventral tegmental area will be studied. The fourth specific aim will determine if selected parameters (assessed post-mortem) which were shown to correlate with novelty-induced locomotion also correlate with amount of amphetamine self-administered previously in an operant chamber. These studies may substantially enhance our knowledge of the possible biochemical bases of drug abuse and addiction, and therefore increase the prospects for rational therapeutic intervention.

在人类的临床状况和药物滥用动物模型中， 个人之间的数量有实质性差异 药物消耗。 试图了解药物的神经生物学 滥用和弃权后复发，生化相关性 在老鼠中对苯丙胺自我给药的脆弱性将是 研究。 这些研究将扩大最新发现，证明 某些行为措施（新颖性和苯丙胺引起的 运动）预测由苯丙胺自我管理的量 动物。 由于中含多巴胺系统在 支持自我管理和苯丙胺引起的运动， 这些研究将主要关注该系统。 该提议是基于的 关于动物之间个体差异的假设 使一些更容易受到毒品自我管理的影响反映在 可测量的生化差异。 两者的可测量索引 伏隔核中突触后多巴胺能传播将是 检查。 该提案有四个基本目标。 第一个将是 确定突触前多巴胺功能的程度差异 与新颖性和苯丙胺诱导的运动的差异相关。 特定的实验将检查苯丙胺诱导的多巴胺释放 通过微透析探测器局部灌注后的体内：2） 苯丙胺诱导的多巴胺在体外释放； 3）全组织测量 在基础条件下多巴胺和代谢产物； 4）多巴胺吸收网站 密度。 第二个特定目的检查突触后的机制 伏隔核中的多巴胺能作用与 行为预测因素：1）伏伏胺的多巴胺受体结合和 纹状体，2）多巴胺受体介导的循环AMP的变化 伏隔族和纹状体组织体外，3）γ-氨基丁酸 受体结合在腹侧颗粒中。 第三个特定目标将 确定行为预测因素与以下的相关性 试图确定行为程度的措施 敏化“在单个动物中：1）全身苯丙胺诱导的 多巴胺在体内释放，通过微透析在清醒大鼠中测量：2） 吗啡诱导的运动和多巴胺在体内释放； 3）压力 （新颖）诱发前额叶细胞外多巴胺的增加 皮层和伏拟核。 G蛋白水平将确定 与新颖性引起的运动，新颖性和苯丙胺的相关性 诱发细胞外多巴胺的增加和百日咳的影响 将研究腹侧对接区域的毒素治疗。 第四 具体目标将确定是否选定的参数（验尸后评估） 证明与新颖性引起的运动相关 与以前在 操作室。 这些研究可能会大大增强我们对 药物滥用和成瘾的可能生化基础，因此 增加理性治疗干预的前景。