Ontogeny of behavioral sensitization: associative and nonassociative processes

描述（由申请人提供）：反复暴露于精神兴奋剂药物（例如，可卡因）导致行为敏化和条件活动的相关现象。在成年大鼠中，联想和非联想过程对这些现象都很重要，尽管介导这些过程的大脑区域是不确定的。另一方面，年轻的大鼠不表现出成年人一样的行为敏感化和条件活动。当药物预处理在一天发生时（即，“一次性”范例）。具体而言，成年大鼠将表现出条件活动和上下文依赖性，但不是上下文无关的，敏化后，一个单一的可卡因预处理;而年轻的大鼠表现出强大的上下文依赖性和上下文无关的敏化，没有条件活动。为了解释这种结果模式，我们假设单一的精神兴奋剂暴露既不启动幼鼠的兴奋性联想过程（即，说明缺乏条件活性）也不启动抑制性联合过程（即，考虑到上下文无关敏化的发生）。这项拨款建议的目的是区分神经机制的背景依赖和背景独立的敏化和条件活动。将研究成年和年轻大鼠，因为行为敏化和条件活动的年龄依赖性差异可用作进一步阐明这些现象背后的神经机制的工具。初始实验的目的是（a）确定什么样的环境线索（如果有的话）是幼年大鼠表现出行为敏化所必需的（具体目标1），以及（B）确定“一次性”行为敏化和条件活动在幼年和成年大鼠中的持续性（具体目标2）。在完成条件活动和致敏试验后，通过测量Fos免疫反应性的区域差异来检查行为致敏的神经基础（具体目标3）。Fos免疫反应性的模式被假设为根据年龄而不同，只有成年大鼠预测表现出增加Fos免疫反应性的大脑区域介导的关联组件的行为敏化和条件活性。其次，将利多卡因显微注射到成年和幼年大鼠的不同脑区，以确定行为敏化和条件活动的关联和非关联成分的神经机制是否可以被解析（具体目标4）。第三，PKC对联想学习很重要，因此具体目标5将确定PKC抑制剂（白屈菜红碱）是否会减弱幼年和成年大鼠行为敏化和条件活动的联想和/或非联想成分。从这些不同的实验结果将显着提高我们的知识有关的个体发育的行为敏化和行为敏化和条件活动的关联和非关联组件的神经机制提供额外的见解。 公共卫生相关性：暴露于精神兴奋剂药物（例如，可卡因和安非他明）产生行为敏化和条件活动。各种脑系统的致敏相关变化可能在药物成瘾中起重要作用。这项拨款提案的目的是评估关联学习的重要性，以及相关的神经变化，参与年轻和成年大鼠的行为敏化和条件活动的发展和持续性。

DESCRIPTION (provided by applicant): Repeated exposure to psychostimulant drugs (e.g., cocaine) results in the related phenomena of behavioral sensitization and conditioned activity. In adult rats, both associative and nonassociative processes are important for these phenomena, although the brain regions that mediate these processes are uncertain. Young rats, on the other hand, do not show adult-like behavioral sensitization and conditioned activity. This fact is most evident when drug pretreatment occurs on a single day (i.e., the "one-shot" paradigm). Specifically, adult rats will exhibit conditioned activity and context-dependent, but not context-independent, sensitization after a single cocaine pretreatment; whereas, young rats show robust context-dependent and context-independent sensitization and no conditioned activity. To account for this pattern of results, we have hypothesized that a single psychostimulant exposure neither initiates an excitatory associative process in young rats (i.e., accounting for the lack of conditioned activity) nor does it initiate an inhibitory associative process (i.e., accounting for the occurrence of context-independent sensitization). The purpose of this grant proposal is to distinguish the neural mechanisms underlying context-dependent and context-independent sensitization and conditioned activity. Both adult and young rats will be studied because age-dependent differences in behavioral sensitization and conditioned activity can be used as a tool for further elucidating the neural mechanisms underlying these phenomena. The purpose of the initial experiments is to (a) determine what environmental cues, if any, are necessary for young rats to exhibit behavioral sensitization (Specific Aim 1), and (b) determine the persistence of "one-shot" behavioral sensitization and conditioned activity in young and adult rats (Specific Aim 2). The neural bases of behavioral sensitization will be examined by measuring regional differences in Fos immunoreactivity after completion of conditioned activity and sensitization testing (Specific Aim 3). The pattern of Fos immunoreactivity is hypothesized to differ according to age, with only adult rats predicted to show increased Fos immunoreactivity in brain areas mediating associative components of behavioral sensitization and conditioned activity. Second, lidocaine will be microinjected into various brain regions of adult and young rats to determine whether neural mechanisms underlying the associative and nonassociative components of behavioral sensitization and conditioned activity can be parsed apart (Specific Aim 4). Third, PKC is important for associative learning so Specific Aim 5 will determine whether a PKC inhibitor (chelerythrine) will attenuate associative and/or nonassociative components of behavioral sensitization and conditioned activity in young and adult rats. Results from these various experiments will significantly enhance our knowledge concerning the ontogeny of behavioral sensitization and provide additional insight about the neural mechanisms underlying the associative and nonassociative components of behavioral sensitization and conditioned activity. Public Health Relevance: Exposure to psychostimulant drugs (e.g., cocaine and amphetamine) produces behavioral sensitization and conditioned activity. Sensitization-related changes in various brain systems may play an important role in drug addiction. The purpose of this grant proposal is to assess the importance of associative learning, and related neural changes, involved in the development and persistence of behavioral sensitization and conditioned activity in young and adult rats.