Neural Substrates of Compulsive Ethanol-Seeking Behavior

描述（由申请人提供）：酒精成瘾是一种以强迫性药物寻求和使用为特征的慢性复发障碍。促成这种行为的一个主要因素是联想学习的过程，即环境刺激与饮酒配对获得激励-动机价值。人们对导致强迫性酒精寻求的过程知之甚少。这一建议的目的是阐明这些过程，重点是识别负责明显强迫性酒精寻求的神经基质，而不是那些由生存、幸福和“健康”享乐追求所必需的自然奖励驱动的中介行为。为了实现这一目标，我们将采用一种新的行为模型，该模型基于乙醇（EtOH）相关情境线索（条件恢复）引发的酒精寻求表现出显著的持久性，而高度有效的自然奖励（PNR）刺激的激励效应迅速衰减。这种条件恢复的差异持续性将作为分离“强迫样”和“正常”寻求行为的中心模型。基于初步数据，这些研究将针对几个主要的神经系统：下丘脑食欲素/下丘脑分泌素（Orx/Hcrt）和CART（可卡因和安非他明相关转录）系统，以及II组代谢性谷氨酸受体。第二个目标将是确定调节强迫性酒精寻求的新型神经系统。该研究计划采用三种方法来检测和验证特定的大脑部位和神经系统在由etoh相关的情境线索和PNR条件刺激诱导的不同的奖励寻求持久性中的作用：最初，（在SPECIFIC AIM I中），将采用系统的神经映射方法，使用诱导转录因子（ITF）作为标记，区分受EtOH信号激活的大脑部位和对PNR信号有反应的大脑部位。这一战略将在SPECIFIC AIM II中得到补充，直接针对根据初步数据制定了具体假设的信号系统。具体来说，Orx/Hcrt和CART的免疫反应性水平以及mGlu2和mGlu3受体的表达将被确定，以测试这些信号系统在寻求由EtOH和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的差异改变。此外，无论是在Orx/Hcrt和CART的情况下，还是在新系统被确定的情况下，双标记其中一个显示激活的ITF标记将提供对EtOH和PNR提示的激活神经元表型的直接信息。特异性Aims I和II的结果表明，特定脑部位内的信号系统的作用与EtOH与PNR线索诱导的恢复的差异持久性有关，然后将在特异性AIM III中通过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的理解，以及对一般动机行为的神经科学的理解。

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