Novel methods to explore mechanisms of cocaine abuse

探索可卡因滥用机制的新方法

• 批准号: 7634513
• 负责人: Friedbert Weiss
• 金额: $ 42.64万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7634513
• 关键词: Abstinence; Animal Model; Basic Science; Behavior; Brain region; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Complement component C1s; Cues; Disease; Drug Addiction; Extinction (Psychology); Funding; Hypothalamic structure; Immediate-Early Genes; Immunohistochemistry; In Situ Hybridization; Incentives; Maps; Metabotropic Glutamate Receptors; Methods; Modeling; Nature; Neurobiology; Pharmaceutical Preparations; Phase; Recording of previous events; Relapse; Research; Resistance; Rewards; Role; Signal Transduction; Site; Stimulus; System; Thalamic structure; Withdrawal; base; cocaine exposure; drug relapse; drug seeking behavior; hedonic; hypocretin; motivated behavior; neuroadaptation; neurobehavioral; non-drug; novel; novel therapeutic intervention; programs; receptor; relating to nervous system

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.

描述(申请人提供)：在前一个资助期，致力于了解慢性易复发的神经生物学基础的研究提供了关于以下方面的重要线索：(A)在药物线索而不是非药物线索产生持续的强迫性类似寻找行为的动物模型中，可卡因条件刺激与强大的自然奖励的不同影响，以及(B)这种行为的神经基础。这项建议的目的是继续研究慢性易复吸的神经生物学基础，重点是确定导致寻求可卡因的明显强迫性的神经底物，与对生存、福祉和“健康”享乐追求至关重要的自然奖励所驱使的行为进行比较。这些研究将遵循(A)关于第二组代谢性谷氨酸受体(MGluR)、sigma1(C1)受体以及下丘脑增食欲素/下丘脑(Orx/Hcrt)系统在可卡因与自然奖励的条件性刺激效应中的选择性作用的先验假设，以及(B)努力确定在强迫药物寻找中具有选择性作用的其他神经系统。我们将致力于四个主要目标：(1)利用即刻早期基因神经作图方法，精确定位可卡因刺激诱导的“寻找”行为与可口的自然奖赏行为差异持续的神经解剖学基础；(2)利用定量免疫组织化学和原位杂交技术，研究第二组mGluR、C1R和Orx/Hcrt信号在调节与可卡因相关而非自然奖赏相关的“寻找”行为持续中的意义；(3)使用特定部位的药物操作，验证不同大脑区域中第二组mGluR、C1和Orx/Hcrt信号在可卡因条件性刺激与自然奖赏刺激诱导的“寻找”行为的持续中的作用；以及(4)确定与可卡因暴露史相关的靶神经系统内的神经适应是否不仅可以将“强迫性”特征传递给寻求毒品的行为，也可以传递给受自然奖赏刺激激发的行为。这些研究将服务于另一个重要目的，即确定寻求毒品行为和自然奖励行为是否可以追溯到早期(特定目标1)和后期(特定目标4)可卡因戒断阶段的相同神经系统和/或神经适应性变化。毒瘾是一种慢性复发性疾病，其特征是尽管有负面后果，但仍强制寻求和使用药物。这种药物强迫症的一个表现是在禁欲期间持续容易复发。拟议的项目将在基础科学层面上提供有关药物强迫这一关键方面的新信息，预计这最终将与确定可卡因依赖的新治疗目标有关。这包括与新的治疗方法有关的信息，这些新的治疗方法旨在加强自然奖励的激励作用，以便更有效地与药物奖励竞争并取代药物奖励。