The role of cocaine-induced changes in OMPFC neurophysiology in cocaine addiction

与健康对照组相比，可卡因成瘾者眼眶前额叶皮质(OFC)的代谢基础活动降低，对自然奖赏相关刺激的代谢反应也降低。然而，在吸毒者中，当受试者受到与可卡因相关的刺激时，OFC也显示出代谢活动的增加。根据这些和其他观察结果，提出了两项建议。首先，它假设可卡因诱导的可塑性导致一般基础的Fc神经元活动减退。然而，第二，可卡因也选择性地放大OFC传入脑区对药物相关事件的神经元反应强度。这种放大的活性在大小上足以维持甚至放大与药物预测事件相关的OFC放电。拟议项目的目标是使用慢性细胞外记录技术来测试这两个提议(统称为OMPFC假说)。AIMS 1-2将分别测试提案1-2。在目标1中，我们将让三组大鼠接受7天的有限可卡因自我给药(每天2小时)。此后，动物将被分配到三个治疗组中的一个，包括：1)长期接触(LGA)可卡因3天(每天6小时)，2)LGA可卡因21天，以及3)LGA可卡因21天和戒断30天。在每次治疗结束时，我们将使用慢性细胞外记录程序记录OFC神经元的基础放电频率。我们还将记录神经元对药物预测线索和药物指导行为的反应。另外三个对照组将接受类似的治疗，只是他们将自我注射蔗糖而不是可卡因。AIM 2的方案将与AIM 1相同，只是记录将在主要的直接OFC传入，即基底外侧杏仁核进行。根据OMPFC假说，预测长期的可卡因暴露和可卡因暴露加长期戒断将导致OFC神经元的平均基础放电减少，但OFC神经对药物相关线索和操作行为的时相反应增加。同样的治疗也有望增加杏仁核对可卡因相关线索和行为的反应强度。在任何蔗糖对照组中都没有观察到神经活动的变化。这一发现将与OMPFC假说一致，并反映出我们在理解药物成瘾的基础机制方面取得的重要进展。

Cocaine addicts exhibit decreased metabolic basal activity in the orbitofrontal cortex (OFC), as well as decreased metabolic responses to natural reward associated stimuli, relative to healthy controls. However, in addicts, the OFC also shows increased metabolic activity when the subjects are presented with cocaine-associated stimuli. Based on these and other observations two proposals have been put forth. First, it is hypothesized that cocaine-induced plasticity induces a general basal OFC neuronal hypoactivity. However, and second, cocaine also selectively amplifies the strength of neuronal responses to drug-associated events in OFC afferent brain regions. This amplified activity is sufficient in magnitude to maintain or perhaps even amplify OFC firing associated with drug-predictive events. The goal of the proposed project is to use chronic extracellular recording techniques to test these 2 proposals (collectively referred to as the OMPFC hypothesis). Aims 1-2 will test proposals 1-2 respectively. In Aim 1, we will expose three groups of rats to 7 days of limited access cocaine self-administration (2 hrs per day). Thereafter, animals will be assigned to one of three treatment groups, including: 1) 3 days of long-access (LgA) cocaine (6-h per day), 2) 21 days of LgA cocaine, and 3) 21 days of LgA cocaine and 30 days of abstinence. At the end of each treatment, we will use chronic extracellular recording procedures to record basal firing rates of OFC neurons. We will also record the response of the neurons to drug-predictive cues and drug-directed behavior. Three additional control groups will be similarly treated except that they will self-administer sucrose instead of cocaine. The protocol of Aim 2 will be the same as Aim 1 except that recordings will be made in a primary direct OFC afferent, the basolateral amygdala. Based on the OMPFC hypothesis, it is predicted that extended cocaine exposure and cocaine exposure plus extended abstinence will induce a decrease in average basal firing of OFC neurons but an increase in phasic OFC neural responses to drug-associated cues and operant behavior. The same treatments are also expected to increase the strength of amygdala responses to cocaine-associated cues and behavior. No changes in neural activity will be observed in any of the sucrose control groups. The findings would be consistent with the OMPFC hypothesis and reflect an important advance in our understanding of mechanisms that underlie drug addiction.