Cocaine Addiction and the Role of Serotonin in Orbitofrontal Cortex Function

使用全细胞电生理学在脑切片中，我们发现，5-HT 1A和5-HT 2A受体激活的生理效应显着降低后，无论是可卡因自我管理（CSA）或轭可卡因管理（CYA）在锥体神经元中的撤退。此外，这些减少5-HT在这些受体的影响持续了许多周后，可卡因戒断，这表明他们可能参与可卡因成瘾的长期方面，如药物渴望。 由于OFC中的5-HT与行为灵活性，学习和其他认知能力有关，我们的实验提供了关于5-HT在可卡因成瘾中所起作用的新信息，以及在可卡因成瘾和戒断期间所表现出的决策受损中所起的作用。 此外，由于5-HT与几种神经精神障碍有关，如抑郁症、焦虑症、痴呆、冲动-攻击性障碍（IAD）、强迫症（OCD）和创伤后应激障碍（PTSD），这些实验提供了关于靶向OFC中的5-HT系统作为潜在疗法的临床效用的有价值的信息。 我们最近在这个项目中的努力集中在开发一个转基因大鼠模型，这将使我们能够检查的作用，5-HT在一类重要的神经元在OFC的调节，被称为快速尖峰（FS），parvalbumin（PV），interneurons。 这些神经元在眶额皮层的总细胞群中占少数，但它们很重要，因为它们使用抑制性神经递质γ-氨基丁酸（GABA），通过广泛的突触连接来协调更大的锥体神经元群的活动。 因此，这些神经元对于正常OFC功能所必需的计算过程是不可或缺的，并且很可能涉及该大脑所贡献的精神病和成瘾性疾病。 为了研究这些神经元，我们的转基因核心已经开发了一种大鼠模型，其中PV基因启动子驱动cre重组酶的表达。 这允许选择性表达荧光蛋白和视蛋白，如channelrhodopsin-2（ChR 2），使我们能够研究这些神经元，并利用光操纵它们的活动。 我们目前的实验集中在脑切片中这些PV细胞的特征，并在定义5-HT受体在调节其活性的影响。 我们也开始确定CSA是否改变这些PV神经元的基础功能，以及CSA是否改变5-HT对这类细胞的影响。希望这些神经元在精神疾病和成瘾中的作用的鉴定将有助于开发用于人类治疗的新的靶向治疗方法。

Using whole-cell electrophysiology in brain slices, we find that physiological effects of 5-HT1A and 5-HT2A receptor activation were dramatically reduced following withdrawal of either cocaine self-administration (CSA) or yoked cocaine administration (CYA) in pyramidal neurons. Moreover, these reduced effects of 5-HT at these receptors persisted for many weeks after cocaine withdrawal, suggesting they may be involved in long-term aspects of cocaine addiction, such as drug craving. As 5-HT in the OFC is implicated in behavioral flexibility, learning and other cognitive abilities, our experiments provide novel information as to the role that 5-HT plays in cocaine addiction, and in the impaired decision-making exhibited during cocaine addiction and withdrawal. In addition, since 5-HT is linked to several neuropsychiatric disorders, such as depression, anxiety, dementia, impulsive-aggression disorder (IAD), obsessive-compulsive disorder (OCD), and post-traumatic stres disorder (PTSD), these experiments provide valuable information as to the clinical utility of targeting the 5-HT system in the OFC as potential therapies. Our recent efforts in this project have focused on developing a transgenic rat model that will permit us to examine the role of 5-HT in the regulation of a class of important neurons in the OFC, known as fast-spiking (FS), parvalbumin (PV), interneurons. These neurons constitute a minority of the total cell population in the OFC, but are important because they use the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), to coordinate the activity of the much larger population of pyramidal neurons, via extensive synaptic connections. Therefore, these neurons are integral to the computational processes that are necessary for normal OFC function, and are likely to be involved in psychiatric and addiction disorders in which this brain are contributes. To study these neurons our transgenic core has developed a rat model in which the PV gene promoter drives the expression of cre recombinase. This permits selective expression fluorescent proteins and opsins, such as channelrhodopsin-2 (ChR2), that allows us to study these neurons, and manipulate their activity with light. Our current experiments have focused on the characterization of these PV cells in brain slices, and in defining the effects of 5-HT receptors in the regulation of their activity. We have also begun to determine whether CSA alters the basal function of these PV neurons, and whether CSA alters the effects of 5-HT on this class of cell. It is hoped that the identification of the roles of these neurons in psychiatric illness and addiction will aid in developing novel targeted therapeutic approaches for treatment in humans.