Role of Prefrontal Networks in Addiction Endophenotypes

描述（由申请人提供）：药物成瘾的定义特征之一是强迫性药物寻求，当它对个人无效或有害时。直到最近，研究药物寻求的神经基础的动物模型很少关注个体之间差异表现的成瘾相关的内表型特征。成瘾治疗的发展取决于对成瘾者和非成瘾者大脑中发生的变化的理解。该计划的目标是研究强迫性药物寻求的个体差异的神经基础。随着可卡因的自我给药，我们将采用最近描述的行为模型，使用成瘾相关的内表型集群来识别成瘾或非成瘾个体。在这些模型中，根据在一系列测试中引入的不同类型冲突中它们坚持寻求可卡因的强烈程度，可以可靠地识别出这些老鼠。测试和测量的内表型包括：递进比（花费努力的意愿），在成对的厌恶刺激存在时的寻求（对负面结果的抵抗），以及在非药物期间的寻求（尽管已知没有药物的坚持）。我们将重点关注前额皮质（PFC）中的差异神经元适应。在人类和动物中，PFC一直与驱动和抑制药物寻找有关，PFC功能失调被认为是成瘾发展的一个主要因素。然而，尚不清楚这种异质结构的不同区域（例如，大鼠的扣带皮层、前边缘皮层、边缘下皮层和眶额皮质）如何相互作用来调节成瘾个体的药物寻求。为了解决这个问题，我们将同时记录大鼠在自我给药和上述成瘾特征测试中这四个PFC区域中多个单个神经元的活动。大鼠将在早期（~2周）和晚期（~7周）进行测试和记录，以监测与成瘾内表型发病相关的PFC神经活动。我们假设，更直接参与驱动药物寻求行为的PFC区域（前边缘和眼窝额叶）将放大成瘾个体的寻找相关活动，并随着时间的推移而增强。我们还假设，在成瘾的大鼠中，PFC区域更多地参与抑制药物寻求行为（边缘下和扣带），随着时间的推移，其活动会逐渐减弱。这种可塑性的双重性质：寻求相关回路的加强和抑制相关回路的减弱被认为是成瘾者获得药物的强迫驱动的关键组成部分。这些研究为研究与成瘾相关的神经可塑性提供了新的途径，并将为成瘾特异性治疗的潜在目标提供有价值的数据。

DESCRIPTION (provided by applicant): One of the defining characteristics of drug addiction is compulsive drug seeking when it is ineffective or detrimental for the individual to do so. Animal models investigating the neural basis of drug seeking have, until recently, focused little attention on characterizing addiction-related endophenotypes that differentially manifest across individuals. The development of treatments for addiction is dependent on understanding what changes occur in the brains of addicted vs. non-addicted individuals. The goal of the proposed project is to investigate the neural basis of individual differences in compulsive drug seeking. Along with cocaine self-administration, we will employ recently-described behavioral models that use clusters of addiction-related endophenotypes to identify individuals as addict-like or non-addict. In these models, such rats are reliably identified based on how strongly they persist in seeking cocaine under different types of conflict introduced in a battery of tests. The tests and the endophenotypes measured include: progressive ratio (willingness to expend effort), seeking in the presence of a paired aversive stimulus (resistance to negative outcomes), and seeking during a non-drug period (persistence despite known absence of drug). We will focus on differential neuronal adaptations in the prefrontal cortex (PFC). The PFC is consistently implicated in both driving and inhibiting drug seeking in humans and animals, and dysregulation of PFC function is thought to be a major factor in the development of addiction. It is not clear, however, how different regions of this heterogeneous structure (e.g., cingulate, prelimbic, infralimbic, and orbitofrontal cortices in the rat) interact to regulate drug seeking in addicted individuals. To address this issue, we will record the activity of multiple single neurons in each of these four PFC regions simultaneously in rats during both self-administration and performance of the addiction-characterizing tests described above. Rats will be tested and recorded during an early (~2 weeks) and late (~7 weeks) session in order to monitor PFC neural activity related to the onset of addiction endophenotypes. We hypothesize that PFC areas more directly involved in driving drug-seeking behavior (prelimbic and orbitofrontal) will have amplified seeking-related activity in addict-like individuals that strengthens over time. We also hypothesize that PFC regions more involved in inhibiting drug seeking behavior (infralimbic and cingulate) will display a gradual weakening of activity over time in addict-like rats. The dual nature of this plasticity: the strengthening of seeking-related circuits and weakening of inhibition-related circuits is proposed to be a key component of the compulsive drive to obtain drugs in addicts. These studies constitute a novel way to investigate the neural plasticity related to addiction and will produce valuable data addressing potential targets for addiction-specific treatments. . PUBLIC HEALTH RELEVANCE: Addiction to cocaine and other drugs of abuse is a serious public health concern. Addiction develops through changes in the neural circuitry that controls motivation and decision-making, ultimately leading to compulsive drug seeking irrespective of the consequences. The proposed experiments will investigate what changes occur in the prefrontal cortex over the development of addiction with the goal of identifying targets for treatment of this disease.