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，造成巨大的生物医学和社会成本。 这些成瘾状态的发作特征是反复接触滥用药物的周期， 随后是戒断/禁欲和再次接触。因此，这些周期可能是 慢性复发性疾病。内源性阿片类神经肽的持续适应， 阿片受体系统（例如，前强啡肽[Pdyn]、MOP-r和KOP-r）， 中脑边缘系统通路是由于暴露于海洛因或可卡因以及从中戒断而发生的。它 假设这些神经生物学变化是自我给药倾向增加的基础 药物，或增加的倾向，升级这种自我管理后，再暴露。的神经生物学 无法直接研究慢性接触、戒断和再接触的标准化周期的影响， 人类，并且尚未在实验动物中进行系统研究。因此，本报告的主要目的 该项目是为了确定动态神经生物学变化（在mRNA和蛋白质水平上， 在慢性（14天）递增循环的特定阶段， 接触海洛因或可卡因，随后长期（14天）戒断和慢性（14天）再接触 滥用药物，模拟成瘾样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的奖励相关功能的变化（在自我管理和 条件性位置偏好测定），其发生在暴露、戒断和再暴露的限定阶段 (Aims 2和3）。对小鼠的进一步研究将确定这种成瘾样循环的类似变化， 关于海洛因、可卡因和阿片类神经肽对多巴胺水平的关键神经化学作用， 在这些多巴胺能通路的终端领域（目的4）。用RNA“敲低”靶向基因 使用MOP-r或Pdyn特异性siRNA的干扰将针对含有MOP-r或Pdyn的细胞体的区域， 在慢性接触之前或戒断开始时，通过上述途径（目标5）。这些siRNA 研究将确定“击倒”干预是否能阻断神经生物学、神经化学或 在海洛因成瘾样周期的特定阶段发生的与奖励相关的行为变化， 可卡因局部施用的药理学探针（例如，阿片受体拮抗剂）将用于 证实了用siRNA敲低机制鉴定的潜在药理学方法。这 该提案将确定神经生物学变化的基础上成瘾样循环的暴露， 戒断和重新接触海洛因或可卡因，并将确定药物管制的目标 在这样的阶段进行干预。为达致协同作用，本项目（目标1）的研究将采用与 本中心的项目2（目标2）（并将侧重于压力反应系统在此环境中的影响）。

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).