Ontogeny of behavioral sensitization: associative and nonassociative processes

描述（由申请人提供）：反复接触精神兴奋剂药物（如可卡因）会导致相关的行为致敏和条件性活动现象。在成年大鼠中，联合和非联合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，幼鼠没有表现出成年鼠的行为敏化和条件活动。当药物预处理在一天内进行时（即“一次性”范例），这一事实最为明显。具体来说，成年大鼠在单一可卡因预处理后会表现出条件活动和情境依赖，但不是情境独立的致敏；然而，年轻大鼠表现出强大的环境依赖性和环境非依赖性敏化和无条件活动。为了解释这种结果模式，我们假设，在年轻的大鼠中，单一的精神兴奋剂暴露既不会启动兴奋性联想过程（即，说明缺乏条件活动），也不会启动抑制性联想过程（即，说明上下文无关敏化的发生）。这项拨款提案的目的是区分上下文依赖性和上下文非依赖性敏化和条件活动的神经机制。成年鼠和幼鼠都将被研究，因为行为敏化和条件活动的年龄依赖性差异可以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)确定什么环境线索（如果有的话）是幼年大鼠表现出行为致敏所必需的（具体目标1），(b)确定“一次性”行为致敏和条件活动在幼年和成年大鼠中的持久性（具体目标2）。行为致敏的神经基础将通过测量完成条件活动和致敏试验后Fos免疫反应性的区域差异来检查（Specific Aim 3）。假设Fos免疫反应模式根据年龄而不同，只有成年大鼠在调节行为致敏和条件活动相关成分的脑区显示Fos免疫反应增加。其次，将利多卡因微注射到成年和年轻大鼠的不同脑区，以确定行为致敏和条件活动的联想和非联想成分的神经机制是否可以分开分析（Specific Aim 4）。第三，PKC对联想学习很重要，因此Specific Aim 5将确定PKC抑制剂（chelerythrine）是否会减弱幼年和成年大鼠行为致敏和条件活动的联想和/或非联想成分。这些不同实验的结果将显著提高我们对行为敏化的个体发生的认识，并为行为敏化和条件活动的联想和非联想成分的神经机制提供额外的见解。

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.