Role of Prefrontal Networks in Addiction Endophenotypes

描述(由申请人提供)：吸毒成瘾的定义特征之一是强迫寻求药物，当这种行为对个人无效或有害时。直到最近，研究寻求毒品的神经基础的动物模型很少关注与成瘾相关的内表型，这些内表型在不同个体之间表现不同。成瘾治疗方法的发展依赖于了解成瘾者和非成瘾者大脑中发生的变化。该项目的目标是研究强迫性药物寻求中个体差异的神经基础。与可卡因自我给药一起，我们将采用最近描述的行为模型，该模型使用与成瘾相关的内表型簇来识别个体是否类似成瘾者。在这些模型中，根据在一系列测试中引入的不同类型的冲突下，这些老鼠坚持寻找可卡因的强度，可以可靠地识别这些老鼠。测试和测量的内在表型包括：递进比率(愿意付出努力)，在一对厌恶刺激存在的情况下寻求(对负面结果的抵抗力)，以及在非药物时期寻求(尽管已知没有药物，但仍坚持)。我们将专注于前额叶皮质(PFC)的不同神经元适应。在人类和动物中，PFC一直被认为与驱动和抑制药物寻找有关，PFC功能的失调被认为是成瘾发生的主要因素。然而，目前还不清楚这种不同结构的不同区域(例如，大鼠的扣带回、前额叶、下缘和眶前叶皮质)如何相互作用来调节成瘾者的药物寻找。为了解决这个问题，我们将记录大鼠在自我给药和执行上述成瘾特征测试期间，这四个PFC区域中每一个区域的多个单一神经元的活动。大鼠将在早期(~2周)和晚期(~7周)进行测试和记录，以监测与成瘾开始相关的PFC神经活动。我们假设，PFC区更直接地参与驱动药物寻找行为(初步和眼眶前额叶)，将放大成瘾者类个体的寻求相关活动，并随着时间的推移而增强。我们还假设，在成瘾大鼠中，参与抑制药物寻找行为的PFC区域(下缘和扣带)将随着时间的推移显示出逐渐减弱的活性。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吸毒者获得毒品的强迫动力的关键组成部分。这些研究构成了研究与成瘾相关的神经可塑性的一种新方法，并将产生有价值的数据，为成瘾特异性治疗提供潜在靶点。。

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. .