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，其特征是强迫性药物寻求和使用。促成这种行为的一个主要因素是联想学习的过程，即环境刺激与酒精消费相结合获得激励激励价值。我们对导致乙醇寻求的强迫性本质发展的过程知之甚少。这个建议的目的是阐明这些过程，重点是确定神经基板负责的明显的强迫性质的酒精寻求，而不是那些调解行为的自然奖励的生存，幸福和“健康”的享乐追求必不可少的动机。为了实现这一点，一个新的行为模型将采用的基础上观察，酒精寻求引起的乙醇（乙醇）相关的上下文线索（条件恢复）显示出显着的持久性，而条件刺激的激励效果，以高效的自然奖励（PNR）衰减迅速。这种条件性恢复的差异性持久性将作为将“强迫样”寻求行为与“正常”寻求行为分离的中心模型。根据初步数据，这些研究将针对几个主要的神经系统：下丘脑食欲素/下丘脑泌素（Orx/Hcrt）和CART（可卡因和安非他明相关转录本）系统，以及II组代谢型谷氨酸受体。第二个目标将是确定新的神经系统，调节强迫性乙醇寻求。该研究计划采用三种融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的差异持久性中的作用，该差异持久性表征了由EtOH相关的上下文线索与PNR条件刺激诱导的恢复：起初，（具体目标一），将采用系统的神经映射方法来区分由EtOH提示激活的脑部位与响应PNR提示的脑部位，使用诱导转录因子（ITF）作为标记。这一策略将在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的假设。具体而言，将确定Orx/Hcrt和CART免疫反应性以及mGlu 2和mGlu 3受体表达的水平，以测试这些信号传导系统在由EtOH与PNR线索诱导的寻找行为中的差异作用是否可以追溯到不同脑部位内的差异改变。此外，在Orx/Hcrt和CART以及新系统被鉴定的情况下，用显示激活的ITF标记之一进行双标记将提供关于响应于EtOH与PNR线索而显示激活的神经元表型的直接信息。特定目的I和II的结果表明，EtOH与PNR线索诱导的恢复差异持久性中涉及的特定脑部位内信号传导系统的作用，然后将通过特定目的III中的部位特异性药理学操作进行验证。该研究计划的目的是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，其特征是强迫性药物寻求和使用。该提案的目的是确定导致寻求酒精的明显强迫性的神经解剖学和神经药理学基质，而不是那些调节由生存、福祉和“健康”享乐追求所必需的自然奖励激发的行为的基质。这项研究有望（a）促进对酒精依赖生物学基础的理解，（B）揭示酒精滥用和酒精中毒的新治疗靶点，（c）促进对正常和病理性目标导向行为的基础科学理解，总的来说

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