Novel methods to explore mechanisms of cocaine abuse

描述（由申请人提供）：在之前的资助期间，致力于理解慢性复发易感性的神经生物学基础的研究已经提供了关于(a)在动物复发模型中，药物线索（而非非药物线索）产生持久的、强迫性的寻求行为的情境刺激与强自然奖励的差异效应，以及(b)这种行为的神经基础。本提案的目标是继续研究慢性易感性复发的神经生物学基础，重点是识别负责可卡因寻求的明显强迫性本质的神经基质，与生存、幸福和“健康”享乐追求所必需的自然奖励驱动的行为相比较。这些研究将以(a)关于II组代谢性谷氨酸受体（mGluR）、sigma1 （C1）受体以及下丘脑食欲素/下丘脑分泌素（Orx/Hcrt）系统的选择性作用的先验假设及其对室旁丘脑的投射为指导，在可卡因与自然奖励的条件激励效应中，以及(b)努力确定在强迫性药物寻求中具有选择性作用的其他神经系统。研究的四个主要目标是：(1)利用即时早期基因神经定位方法，确定可卡因刺激与高度可口的自然奖励诱导的“寻求”行为差异持续性的神经解剖学基础；(2)利用定量免疫组织化学和原位杂交技术，研究II组mGluR、C1受体和Orx/Hcrt信号在调节与可卡因相关而非自然奖励相关的“寻找”行为的持续性中的意义；(3)利用特定部位的药理学操作，验证II组mGluR、C1和Orx/Hcrt信号在不同脑区的作用，在可卡因刺激与自然奖励诱导的“寻求”行为的持续中；(4)确定与可卡因暴露史相关的目标神经系统内的神经适应性是否不仅可以向寻求药物的行为传达“强迫性”特征，还可以向自然奖励条件下的刺激行为传达“强迫性”特征。这些研究将有一个额外的重要目的，即确定药物寻求行为和由自然奖励驱动的行为是否可以追溯到早期（特定目标1）和后期（特定目标4）可卡因戒断阶段相同的神经系统和/或神经适应性变化。药物成瘾是一种慢性复发的疾病，其特征是强迫性药物寻求和使用，尽管有负面后果。这种药物强迫症的表现之一是在戒断期间持续易复发。拟议的项目将在基础科学一级提供关于药物强迫这一关键方面的新信息，预计这些信息最终将与确定可卡因依赖的新治疗目标有关。这包括与新治疗方法相关的信息，旨在增强自然奖励的激励显著性，以更有效地与药物来源的奖励竞争和替代。

DESCRIPTION (provided by applicant): Studies during the previous funding period dedicated to understanding the neurobiological basis of chronic vulnerability to relapse have provided important leads with regard to (a) differential effects of contextual stimuli conditioned to cocaine vs. potent natural reward in animal models of relapse where drug cues, but not non-drug cues, produce persistent, compulsive-like seeking behavior, and (b) the neural basis of this behavior. The objective of this proposal is to continue to study the neurobiological basis of chronic vulnerability to relapse with emphasis on identifying neural substrates responsible for the distinctly compulsive nature of cocaine-seeking, compared to behavior motivated by natural rewards essential for survival, well being, and "healthy" hedonic pursuits. These studies will be guided by (a) a priori hypotheses on a selective role of Group II metabotropic glutamate receptors (mGluR), the sigma1 (C1) receptor, as well the hypothalamic orexin/hypocretin (Orx/Hcrt) system and its projection to the paraventricular thalamus in the conditioned incentive effects of cocaine vs. natural reward, and (b) efforts to identify additional neural systems with a selective role in compulsive drug-seeking. Four major objectives will be pursued: (1) To pinpoint neuroanatomical substrates of the differential persistence of "seeking" behavior induced by stimuli conditioned to cocaine vs. highly palatable natural reward using immediate early gene neural mapping approaches; (2) to investigate the significance of Group II mGluR, C1 receptor, and Orx/Hcrt signaling in the regulating the persistence of "seeking" behavior associated with cocaine but not natural reward using quantitative immunohistochemistry and in situ hybridization; (3) to verify a role of Group II mGluR, C1, and Orx/Hcrt signaling within distinct brain regions in the persistence of "seeking" behavior induced by stimuli conditioned to cocaine vs. natural reward, using site-specific pharmacological manipulations; and (4) to establish whether neuroadaptation within the targeted neural systems associated with a history of cocaine exposure can convey "compulsive" character not only to drug-seeking behavior, but also behavior motivated by stimuli conditioned to natural reward. These studies will serve the additional important purpose of establishing whether drug-seeking behavior and behavior motivated by natural reward can be traced to the same neural systems and/or neuroadaptive changes during early (Specific Aim 1) vs. later (Specific Aim 4) cocaine abstinence phases. Drug addiction is a chronically relapsing disorder characterized by compulsive drug-seeking and use despite negative consequences. One manifestation of this drug compulsion is persistent vulnerability to relapse during abstinence. The proposed project will provide novel information on this critical aspect of drug compulsion at the basic science level that is expected to be relevant, ultimately, for the identification of novel treatment targets for cocaine dependence. This includes information relevant for novel therapeutic approaches aimed at enhancing the incentive salience of natural rewards to more effectively compete with and substitute for drug-derived reward.