Ontogeny of behavioral sensitization: associative and nonassociative processes

描述(申请人提供)：反复接触精神刺激性药物(如可卡因)会导致行为敏感化和条件性活动的相关现象。在成年大鼠中，联想和非联想过程对这些现象都很重要，尽管参与这些过程的大脑区域尚不确定。另一方面，幼鼠不会表现出成人般的行为敏感化和条件性活动。这一事实在药物预处理发生在一天内时最为明显(即“一次性”范例)。具体地说，成年大鼠在一次可卡因处理后将表现出条件活动和上下文依赖的敏化，但不是上下文无关的敏化；而幼鼠则表现出强烈的上下文依赖和上下文无关的敏化，而没有条件性活动。为了解释这种结果模式，我们假设，单一的精神刺激剂暴露既不会在幼年大鼠中启动兴奋性联想过程(即，解释缺乏条件性活动)，也不会启动抑制性联想过程(即，解释上下文无关敏化的发生)。这项赠款提案的目的是区分上下文依赖和上下文无关的敏感化和条件化活动的神经机制。成年大鼠和幼年大鼠都将被研究，因为行为敏感化和条件性活动的年龄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。初步实验的目的是(A)确定幼年大鼠表现出行为敏化所必需的环境线索(特定目标1)，以及(B)确定幼年和成年大鼠“一次性”行为敏化和条件性活动的持续性(特定目标2)。行为敏化的神经基础将在完成条件性活动和敏化测试(特定目标3)后通过测量Fos免疫反应的区域差异来检验。Fos免疫反应的模式被假设随着年龄的不同而不同，只有成年大鼠被预测在参与行为敏化和条件性活动的相关成分的脑区显示出Fos免疫反应增强。其次，利多卡因将被显微注射到成年和幼年大鼠的不同大脑区域，以确定行为敏感化和条件化活动的关联和非关联成分背后的神经机制是否可以被解析出来(特定目标4)。第三，PKC对联想学习很重要，因此特定的目标5将决定PKC抑制剂(白屈菜红碱)是否会减弱幼年和成年大鼠行为敏感化和条件化活动的关联和/或非关联成分。这些不同实验的结果将大大增强我们对行为敏感化个体发生的了解，并为行为敏感化和条件化活动的关联和非关联成分的神经机制提供更多的见解。 与公共卫生的相关性：接触精神刺激药物(如可卡因和苯丙胺)会产生行为敏感化和条件性活动。不同大脑系统的敏化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联想学习和相关的神经变化的重要性，这些变化涉及幼年和成年大鼠行为敏感化和条件化活动的发展和持续。

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.