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

与健康对照组相比，可卡因成瘾者眶额皮质（OFC）的代谢基础活动降低，对自然奖励相关刺激的代谢反应也降低。然而，在成瘾者中，当受试者受到可卡因相关刺激时，眶额皮层也显示出代谢活动增加。根据这些意见和其他意见，提出了两项建议。首先，它是假设可卡因诱导的可塑性诱导一般基础OFC神经元活动减退。然而，第二，可卡因也选择性地放大了OFC传入脑区神经元对药物相关事件的反应强度。这种放大的活性在幅度上足以维持或甚至放大与药物预测事件相关的OFC放电。该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假设）。目标1-2将分别测试提议1-2。在目标1中，我们将三组大鼠暴露于7天的有限获取可卡因自我给药（每天2小时）。此后，将动物分配至三个治疗组之一，包括：1）3天的长期接触（LgA）可卡因（每天6小时），2）21天的LgA可卡因，和3）21天的LgA可卡因和30天的禁欲。在每次治疗结束时，我们将使用慢性细胞外记录程序来记录OFC神经元的基础放电率。我们还将记录神经元对药物预测线索和药物导向行为的反应。另外三个对照组将进行类似处理，不同之处在于它们将自我给予蔗糖而不是可卡因。目标2的方案将与目标1相同，除了记录将在初级直接OFC传入（基底外侧杏仁核）中进行。基于OMPFC假说，预测长期可卡因暴露和可卡因暴露加长期戒断将诱导OFC神经元的平均基础放电减少，但对药物相关线索和操作行为的阶段性OFC神经反应增加。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均未观察到神经活动变化。这些发现与OMPFC假说一致，反映了我们对药物成瘾机制的理解取得了重要进展。

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.