Neural Substrates of Compulsive Ethanol-Seeking Behavior

描述(申请人提供)：酒精成瘾是一种慢性复发性障碍，以强迫寻求和使用药物为特征。造成这种行为的一个主要因素是联想学习的过程，在这个过程中，环境刺激和酒精消费相结合，获得了激励-动机价值。人们对导致寻求酒精这种强迫性本质发展的过程知之甚少。这项建议的目的是阐明这些过程，重点是确定神经底物负责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对生存，福祉和“健康”享乐追求必不可少的动机。为了实现这一点，将采用一种新的行为模型，该模型基于以下观察：由乙醇(Etoh)相关的情境线索(条件化恢复)引发的酒精寻找表现出显著的持久性，而高度有效的自然奖励(PNR)刺激的刺激效应迅速衰减。这种条件性复职的不同持续性将成为区分“强迫症”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：下丘脑增食欲素/下丘脑(Orx/Hcrt)和CART(可卡因和苯丙胺相关转录物)系统，以及第二类代谢性谷氨酸受体。第二个目标将是识别控制强迫性酒精寻求的新神经系统。该研究计划采用了三种融合的方法来检测和验证特定的大脑部位和神经系统在奖赏寻求的不同持续性中所起的作用，该奖赏寻求的特征是由乙醇相关的上下文线索诱导的恢复与受PNR制约的刺激：首先，(在特定的AIM I中)，将使用系统的神经映射方法来区分乙醇线索激活的脑部位和对PNR线索反应的脑部位，使用可诱导转录因子(ITF)作为标记物。这一战略将在特定的AIM II中得到补充，直接针对基于初步数据制定了具体假设的信号系统。具体地说，将测定Orx/Hcrt和CART免疫反应性水平以及mGlu2和mGlu3受体的表达，以测试这些信号系统在Etoh和PNR线索诱导的寻找行为中的不同作用是否可以追溯到不同大脑部位的不同变化。此外，在Orx/Hcrt和CART的情况下，以及新的系统被识别，用显示激活的ITF标记之一的双重标记将提供关于在Etoh和PNR信号反应中显示激活的神经元的表型的直接信息。在特定目标I和II的结果中，特定大脑部位的信号系统在乙醇和PNR线索诱导的不同持续状态中所起的作用，然后将通过特定部位的药理学操作在特定的AIM III中得到验证。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，以及对动机行为的神经科学的总体理解。 与公共卫生相关：酒精成瘾是一种慢性复发性障碍，其特征是强迫寻求和使用药物。这项建议的目的是确定神经解剖学和神经药理学的基础，这些基础负责明显的强迫性酒精寻求，而不是那些以自然奖励为动机的行为，这些自然奖励对生存、福祉和“健康”的享乐追求至关重要。这项研究有望(A)促进对酒精依赖的生物学基础的了解，(B)揭示酒精滥用和酒精中毒的新治疗靶点，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