NEUROPLASTIC ADAPTATIONS ENGENDERED BY DRUGS OF ABUSE

这份申请是为了获得高级科学家奖(K05)，为Terry E.Robinson继续他正在进行的滥用药物引起的神经整形适应及其在成瘾中所起的作用的研究提供工资支持。罗宾逊博士发表了大量关于精神运动兴奋剂对大脑单胺系统和行为的影响，特别是关于精神运动兴奋剂的敏化、停药和神经毒性的研究。最近，他专注于环境刺激调节精神运动敏化的诱导和表达的能力，以及涉及的神经生物学机制。本申请中提出的实验代表了一个新的研究方向。大多数关于敏化的神经生物学研究都集中在神经递质系统的生化适应上。然而，罗宾逊博士和科尔布博士最近报告称，反复使用安非他明或可卡因会导致伏隔核和前额叶皮质神经元上树突和树突的结构发生持续变化，这两个大脑区域与调节药物奖赏有关。这些发现表明，接触精神刺激性药物会改变这些大脑区域的突触连接模式，可能也会改变它们的功能。这里提出的新研究方向的具体目的是进一步表征精神刺激药物改变大脑奖赏区域神经回路的能力(使用高尔基技术)，并确定这些结构适应与精神运动敏化发展相关的程度。在第一系列实验中，将使用各种已知的程序来增加或减少行为敏感化的强度或持久性，以确定结构适应与行为现象共同变化的程度。在第二个研究中，将确定药物自我给药经验是否会对树突结构产生类似于实验者给药的影响，以及自我给药可卡因暴露程度、摄入量增加和形态适应之间的关系。在第三项研究中，将获得更详细的信息，了解精神刺激剂药物引起中等刺突神经元和锥体细胞棘突密度变化的确切位置(即，结构变化仅限于树突树的一部分)，以及其他细胞群是否也受到影响。最后，在第四项研究中，将确定在生命的某个阶段接触精神刺激药物是否会限制受影响的大脑区域在以后的生活中进行结构适应的能力，这是环境条件变化的结果，还是与大脑损伤恢复有关的能力。对于罗宾逊博士来说，这些实验涉及到一种新的方法来研究精神运动敏化，以及药物使用的长期神经生物学后果问题。这就是目前申请KO5的原因。KO5奖将把他的时间从其他部门和大学的责任中解放出来，使他能够专注于开发持久药物效应的解剖学和分子分析方面的新技能。

This application is for a Senior Scientist Award (K05) to provide salary support for Terry E. Robinson to continue his ongoing studies on neuroplastic adaptations engendered by drugs of abuse and the role they play in addiction. Dr. Robinson has published extensively on the effects of psychomotor stimulants on brain monoamine systems and behavior, and especially on psychomotor stimulant sensitization, withdrawal, and neurotoxicity. Recently he has focused on the ability of environmental stimuli to modulate the induction and expression of psychomotor sensitization, as well as the neurobiological mechanisms involved. The experiments proposed in the present application represent a new research direction. Most studies on the neurobiology of sensitization have focused on biochemical adaptations in neurotransmitter systems. Drs. Robinson and Kolb have recently reported, however, that repeated treatment with amphetamine or cocaine produces persistent changes in the structure of dendrites and dendritic spines on neurons in the nucleus accumbens and prefrontal cortex, two brain regions prominently implicated in mediating drug reward. These findings suggest that exposure to psychostimulant drugs alters patterns of synaptic connectivity in these brain regions, presumably also altering their function. The specific aim of the new research direction proposed here is to further characterize the ability of psychostimulant drugs to alter neural circuitry in brain reward regions (using the Golgi technique) and to determine the extent to which these structural adaptations are related to the development of psychomotor sensitization. In the first series of experiments a variety of procedures known to increase or decrease the strength or persistence of behavioral sensitization will be used to determine the extent to which structural adaptations co-vary with the behavioral phenomenon. In the second, it will be determined whether drug self-administration experience produces effects on dendritic structure similar to those seen with experimenter- administered drug, and the relationship between the degree of exposure to self-administered cocaine, escalation of intake and morphological adaptations. In the third, more detailed information will be acquired about the exact locus of psychostimulant drug-induced changes in spine density on medium spiny neurons and pyramidal cells (i.e., are structural changes confined to one portion of the dendritic tree), and whether other cell populations are also affected. Finally, in the fourth, it will be determined whether exposure to psychostimulant drugs at one point in life limits the ability of the affected brain regions to undergo structural adaptations later in life, as a consequence of changes in environmental condition or in association with recovery from brain damage. For Dr. Robinson these experiments involve a new approach to the study of psychomotor sensitization, and to the problem of the long-term neurobiological consequences of drug use. This is the reason for a KO5 application at this time. A KO5 Award would free his time from other departmental and university responsibilities and allow him to concentrate on developing new skills in the anatomical and molecular analysis of persistent drug effects.