Neural Substrates of Compulsive Ethanol-Seeking Behavior

描述（由申请人提供）：酒精成瘾是一种慢性复发性疾病，其特征是强迫性寻求和使用药物。造成这种行为的一个主要因素是联想学习的过程，环境刺激与饮酒相结合获得了激励-激励价值。人们对于导致乙醇寻求的强迫性性质的发展过程知之甚少。该提案的目的是阐明这些过程，重点是确定导致酗酒的明显强迫性质的神经基质，而不是那些由生存、福祉和“健康”享乐追求所必需的自然奖励所驱动的中介行为。为了实现这一目标，我们将采用一种新颖的行为模型，该模型基于以下观察：由乙醇（EtOH）相关的情境线索（条件恢复）引起的酒精寻求表现出显着的持久性，而条件性刺激的高效自然奖励（PNR）的激励效果则迅速衰减。这种条件恢复的差异持续性将成为将“强迫性”与“正常”寻求行为区分开来的中心模型。根据初步数据，这些研究将针对几个主要神经系统：下丘脑食欲素/下丘脑分泌素 (Orx/Hcrt) 和 CART（可卡因和安非他明相关转录物）系统，以及 II 类代谢型谷氨酸受体。第二个目标是确定调节强迫性乙醇寻求的新型神经系统。该研究计划采用三种聚合方法来检测和验证特定大脑部位和神经系统在奖励寻求差异持续性中的作用，其特征是由 EtOH 相关情境线索与 PNR 条件刺激诱导的恢复：最初，（在 SPECIFIC AIM I 中），将采用系统神经映射方法来区分由 EtOH 线索激活的大脑部位与对 PNR 线索响应的大脑部位，使用诱导转录因子（ITF）作为标记。该策略将在 SPECIFIC AIM II 中得到补充，直接针对信号系统，并根据初步数据制定了具体假设。具体来说，将确定 Orx/Hcrt 和 CART 免疫反应性水平以及 mGlu2 和 mGlu3 受体表达，以测试这些信号系统在寻找 EtOH 与 PNR 提示诱导的行为中的差异作用是否可以追溯到不同大脑部位内的差异改变。此外，在 Orx/Hcrt 和 CART 的情况下，以及待识别的新系统，用显示激活的 ITF 标记之一进行双重标记将提供有关响应 EtOH 与 PNR 提示而显示激活的神经元表型的直接信息。通过特定目标 I 和 II 的结果，特定脑位点内信号系统的作用涉及 EtOH 与 PNR 线索诱导恢复的差异持久性，然后将通过特定目标 III 中的位点特异性药理学操作进行验证。该研究计划的制定目的是总体上促进对酒精依赖的生物学基础以及动机行为的神经科学的理解。 公共卫生相关性：酒精成瘾是一种慢性复发性疾病，其特征是强迫性寻求和使用药物。该提案的目的是确定导致酗酒的明显强迫性质的神经解剖学和神经药理学底物，而不是那些由生存、福祉和“健康”享乐追求所必需的自然奖励所驱动的中介行为。这项研究预计将（a）促进对酒精依赖的生物学基础的理解，（b）揭示酒精滥用和酒精中毒的新治疗目标，以及（c）总体上促进对正常和病理性目标导向行为的基础科学理解

DESCRIPTION (provided by applicant): Alcohol addiction is a chronically relapsing disorder characterized by compulsive drug-seeking and use. A major factor contributing to this profile of behavior is the process of associative learning whereby environmental stimuli paired with alcohol consumption acquire incentive-motivational value. Little is known about the processes leading to the development of the compulsive-like nature of ethanol-seeking. The objective of this proposal is to elucidate these processes with emphasis on identifying neural substrates responsible for the distinctly compulsive nature of alcohol-seeking as opposed to those mediating behavior motivated by natural reward essential for survival, well being and "healthy" hedonic pursuits. To accomplish this, a novel behavioral model will be employed based on the observation that alcohol-seeking elicited by ethanol (EtOH) -associated contextual cues (conditioned reinstatement) shows remarkable persistence whereas the motivating effects of stimuli conditioned to highly potent natural reward (PNR) decay rapidly. This differential persistence of conditioned reinstatement will serve as the central model to dissociate "compulsive- like" from "normal" seeking behavior. Based on preliminary data, these studies will target several primary neural systems: The hypothalamic orexin/hypocretin (Orx/Hcrt) and CART (cocaine and amphetamine-related transcript) systems, as well as Group II metabotropic glutamate receptors. A second objective will be to identify novel neural systems that regulate compulsive ethanol-seeking. The research plan employs three converging approaches for detecting and verifying a role of specific brain sites and neural systems in the differential persistence of reward-seeking that characterizes reinstatement induced by EtOH-associated contextual cues vs. stimuli conditioned to PNR: Initially, (in SPECIFIC AIM I), a systematic neural mapping approach will be employed to differentiate brain sites activated by an EtOH cue from those responsive to a PNR cue, using inducible transcription factors (ITF) as markers. This strategy will be complemented in SPECIFIC AIM II by directly targeting the signaling systems about which specific hypotheses have been formulated based on preliminary data. Specifically, levels of Orx/Hcrt and CART immunoreactivity as well as mGlu2 and mGlu3 receptor expression will be determined to test whether a differential role of these signaling systems in seeking behavior induced by the EtOH vs. PNR cue can be traced to differential alterations within distinct brain sites. Additionally, both in the case of Orx/Hcrt and CART, and novel systems be identified, dual-labeling with one of the ITF markers showing activation will provide direct information on the phenotype of neurons showing activation in response to the EtOH vs. PNR cues. A role of signaling systems within specific brain sites implicated in the differential persistence of EtOH vs. PNR cue-induced reinstatement by results of Specific Aims I and II, then will be verified by site-specific pharmacological manipulations in SPECIFIC AIM III. The research plan has been developed with the objective of advancing understanding the biological basis of alcohol dependence, as well as of the neuroscience of motivated behavior, in general. PUBLIC HEALTH RELEVANCE: Alcohol addiction is a chronically relapsing disorder characterized by compulsive drug-seeking and use. The objective of this proposal is to identify neuroanatomical and neuropharmacological substrates responsible for the distinctly compulsive nature of alcohol-seeking as opposed to those mediating behavior motivated by natural reward essential for survival, well being and "healthy" hedonic pursuits. This research is expected to (a) advance understanding the biological basis of alcohol dependence, (b) reveal novel treatment targets for alcohol abuse and alcoholism, and (c) advance basic science understanding of normal and pathological goal- directed behavior, in general