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，当它是无效的或有害的个人这样做。研究药物寻求的神经基础的动物模型，直到最近，很少关注表征成瘾相关的内在表型，在个体之间的差异表现。成瘾治疗的发展取决于了解成瘾与非成瘾个体的大脑发生了什么变化。该项目的目标是研究强迫性药物寻求个体差异的神经基础。沿着可卡因自我给药，我们将采用最近描述的行为模型，该模型使用成瘾相关的内表型集群来识别成瘾样或非成瘾个体。在这些模型中，这些老鼠是根据它们在一系列测试中引入的不同类型的冲突下坚持寻找可卡因的强度来可靠地识别的。测试和测量的内在表型包括：进行性比率（愿意付出努力），在配对厌恶刺激存在下寻求（对负面结果的抵抗力），以及在非药物期间寻求（尽管已知没有药物，但仍持续存在）。 我们将重点讨论前额叶皮层（PFC）的差异神经元适应。PFC始终与人类和动物的药物寻求驱动和抑制有关，PFC功能失调被认为是成瘾发展的主要因素。然而，尚不清楚这种异质结构的不同区域（例如，大鼠的扣带、前边缘、下边缘和眶额皮质）相互作用以调节成瘾个体的药物寻求。为了解决这个问题，我们将在大鼠自我给药和进行上述成瘾表征测试期间同时记录这四个PFC区域中每个区域的多个单个神经元的活性。将在早期（约2周）和晚期（约7周）阶段对大鼠进行测试和记录，以监测与成瘾内表型发作相关的PFC神经活动。我们假设，PFC区域更直接地参与驱动药物寻求行为（前边缘系统和眶额）将扩大寻求相关的活动，随着时间的推移，加强成瘾样个人。我们还假设，PFC区域更多地参与抑制药物寻求行为（边缘下和扣带回）将显示逐渐减弱的活动，随着时间的推移，在成瘾样大鼠。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。这些研究构成了一种新的方式来研究与成瘾相关的神经可塑性，并将产生有价值的数据，解决成瘾特异性治疗的潜在目标。 .

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. .