THE CYCLE OF EXPOSURE, WITHDRAWAL AND RE-EXPOSURE TO HEROIN OR COCAINE:

海洛因或可卡因成瘾是主要的公共卫生问题，具有巨大的生物医学和社会成本。 这些成瘾状态的开始以反复暴露于滥用药物的循环为特征， 然后是戒断/禁欲和再次暴露。因此，这些周期可能是 成瘾作为慢性复发性障碍。内源性阿片神经肽和内源性阿片肽的持续适应 多巴胺能黑质和纹状体中的阿片受体系统(如前强啡肽、MOP-r和Kop-r) 中-边缘通路是由于接触海洛因或可卡因以及戒断这些物质而发生的。它 假设这些神经生物学变化是自我管理倾向增强的基础 药物，或在再次接触时升级这种自我管理的倾向增加。神经生物学 慢性暴露、戒断和再暴露的标准化周期的影响不能直接在#年研究 人类，而且还没有在实验动物中进行系统的研究。因此，这一行动的主要目标是 项目是确定动态的神经生物学变化(在mRNA和蛋白质水平上) 上述和相关靶系统)在慢性(14天)升级周期的特定阶段的大鼠 接触海洛因或可卡因，然后长期(14天)戒断和慢性(14天)再次暴露 关于滥用药物，模拟成瘾循环的神经生物学后果(目标1)。平行 研究将确定海洛因或可卡因与奖励相关的功能变化(自我管理和 条件位置偏好分析)，发生在暴露、戒断和再暴露的特定阶段 (目标2和3)。在老鼠身上的进一步研究将确定类似于这种成瘾循环的变化，也 海洛因、可卡因和阿片类神经肽对多巴胺水平的关键神经化学效应 在这些多巴胺能通路的终末区域(目标4)。用RNA“敲除”靶向基因 使用针对MOP-r或Pdyn的siRNA的干扰将定向到包含Mop-r或Pdyn细胞体的区域 上述途径，要么在慢性暴露之前，要么在戒断开始时(目标5)。这些siRNA 研究将确定“击倒”干预是否可以阻断神经生物、神经化学或 在类海洛因成瘾周期的特定阶段发生的奖赏相关行为变化 可卡因。当地使用的药理探针(如阿片受体拮抗剂)将用于 确认通过siRNA敲除机制确定的潜在药物治疗方法。这 这项提议将决定类似于成瘾的暴露循环背后的神经生物学变化， 戒断和再次接触海洛因或可卡因，并将确定药物治疗的目标 在这样的阶段进行干预。为了发挥协同作用，本项目(目标1)的研究将使用平行方法 该中心的项目2(目标2)(并将重点放在应激反应系统在这一背景下的影响)。

Heroin or cocaine addictions are major public health problems, with massive biomedical and societal costs. The onset of these addictive states is characterized by cycles of repeated exposure to the drug of abuse, followed by withdrawal/abstinence and re-exposure. Therefore these cycles may be cardinal features of addictions as chronic relapsing disorders. Persisting adaptations in endogenous opioid neuropeptide and opioid receptor systems (e.g., prodynorphin [Pdyn], MOP-r and KOP-r) in dopaminergic nigrostriatal and meso-limbic pathways occur as a result of exposure to heroin or cocaine, as well as withdrawal therefrom. It is hypothesized that these neurobiological changes underlie the increased propensity to self-administer drugs, or increased propensity to escalate such self-administration upon re-exposure. The neurobiological effects of a standardized cycle of chronic exposure, withdrawal and re-exposure cannot be directly studied in humans, and have not been systematically studied in experimental animals. Thus, the main objective of this project is to determine dynamic neurobiological changes (at the mRNA and protein level in the aforementioned and related target systems) in rats at specific stages in a cycle of chronic (14-day) escalating exposure to heroin or cocaine, followed by long term (14-day) withdrawal and chronic (14-day) re-exposure to the drug of abuse, modeling the neurobiological consequences of an addiction-like cycle (Aim 1). Parallel studies would define changes to reward-related functions of heroin or cocaine (in self-administration and conditioned place preference assays) that occur at defined stages of exposure, withdrawal and re-exposure (Aims 2 and 3). Further studies in mice would determine analogous changes in this addiction-like cycle, also with respect to critical neurochemical effects of heroin, cocaine and opioid neuropeptides on dopamine levels in terminal fields of these dopaminergic pathways (Aim 4). Targeted gene "knockdown" with RNA interference using siRNAs specific for MOP-r or Pdyn will be directed toward areas containing cell bodies of the above pathways, either prior to chronic exposure, or at the onset of withdrawal (Aim 5). These siRNA studies will determine whether "knockdown" interventions can block neurobiological, neurochemical or reward-related behavioral changes occurring at specific stages of the addiction-like cycle to heroin or cocaine. Locally administered pharmacological probes (e.g., opioid receptor antagonists) will be used to confirm potential pharmacotherapeutic approaches mechanistically identified with siRNA knockdown. This proposal would determine neurobiological changes underlying an addiction-like cycle of exposure, withdrawal and re-exposure to heroin or cocaine, and will identify targets for pharmacotherapeutic intervention in such stages. For synergy, studies in this Project (Aim 1) will use parallel methodology with Project 2 (Aim 2) of this Center (and will focus on the influence of stress-responsive systems in this setting).