Cocaine Addiction and the Role of Serotonin in Orbitofrontal Cortex Function

利用脑片全细胞电生理学方法，我们发现在锥体神经元中，5-HT1A和5-HT2A受体激活的生理效应在停用可卡因自给药(CsA)或交叉可卡因给药(CyA)后显著降低。此外，这些受体上5-羟色胺的减少效应在可卡因戒断后持续了数周，这表明它们可能与可卡因成瘾的长期方面有关，如对药物的渴望。由于OFC中的5-羟色胺与行为灵活性、学习和其他认知能力有关，我们的实验为5-羟色胺在可卡因成瘾中所起的作用以及在可卡因成瘾和戒断过程中表现出的决策障碍提供了新的信息。此外，由于5-羟色胺与多种神经精神障碍有关，如抑郁症、焦虑症、痴呆症、冲动攻击性障碍(IAD)、强迫症(OCD)和创伤后应激障碍(PTSD)，这些实验为将5-羟色胺系统作为潜在治疗方法在OFC中的临床应用提供了有价值的信息。 我们最近在这个项目中的努力集中在开发转基因大鼠模型上，该模型将使我们能够研究5-羟色胺在OFC中一类重要神经元--快峰(FS)、小白蛋白(PV)、中间神经元的调节中的作用。这些神经元在OFC的细胞总数中只占少数，但它们很重要，因为它们使用抑制性神经递质伽马氨基丁酸(GABA)，通过广泛的突触连接来协调更大数量的锥体神经元的活动。因此，这些神经元是正常OFC功能所必需的计算过程的组成部分，并可能参与精神障碍和成瘾障碍，而这一大脑也参与其中。为了研究这些神经元，我们的转基因核心建立了一个大鼠模型，在该模型中，PV基因启动子驱动cre重组酶的表达。这允许选择性地表达荧光蛋白和视蛋白，如通道视紫红质-2(ChR2)，使我们能够研究这些神经元，并利用光来操纵它们的活动。我们目前的实验主要集中在脑片中这些PV细胞的特征，以及确定5-羟色胺受体在调节其活动中的作用。我们还开始确定CsA是否改变了这些PV神经元的基本功能，以及CsA是否改变了5-羟色胺对这类细胞的影响。人们希望，确定这些神经元在精神疾病和成瘾中的作用将有助于开发针对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.