Interrogation of Insular Excitatory/Inhibitory Balance in Cocaine-Associated Cue Reactivity

项目总结/摘要 可卡因使用障碍在美国是一个相当大的健康挑战， 药物治疗。易受环境和毒品相关线索的影响， 可卡因服用行为（“线索反应”）被认为会引发依赖和复发的循环， 可卡因使用障碍的高再犯率。因此，更好地了解其机制， 提示反应是产生新的药物治疗策略以防止可卡因使用复发所必需的 disorder.研究表明，无颗粒岛叶皮质（AIC）可能在调节线索反应性中起关键作用 通过作为解释内感受信号和传递该信息的汇聚点 到皮质纹状体回路中的其他节点。AIC微电路中的兴奋和抑制平衡， 分别由驻留的谷氨酸投射神经元和γ-氨基丁酸（GABA）中间神经元维持， 对它的正常功能至关重要假设皮层兴奋/抑制平衡的改变 成瘾中寻求药物行为的驱动过程。5-羟色胺（5-HT）神经传递通过其 同源Gαq/11蛋白偶联的5-HT 2C受体（5-HT 2CR）在维持皮质 这些受体参与调节兴奋/抑制平衡和调节线索反应性，并且这些受体在AIC中表达。我们 我提出，一个潜在的机制，以抑制线索反应是通过协调的功能 AIC-皮质纹状体回路中的连接，由AIC内的5-HT 2CR系统控制。采用 药物遗传学、生物化学、行为学、遗传学和药理学方法，本研究将 通过两个特定的目的来解决这个假设：1）询问可卡因线索中的AIC皮质纹状体环路 反应性，和2）阐明5-HT 2CR控制AIC线索反应性。复杂规律的阐明 5-HT 2CR对AIC内GABA：谷氨酸神经元相互作用的调节，因为它与提示 反应性将导致更好地理解可卡因使用障碍复发的个体风险因素。这 这些信息将用于指导预防复发的治疗开发，以最终解决这一问题 可卡因使用障碍的治疗。

PROJECT SUMMARY/ABSTRACT Cocaine use disorder is a sizeable health challenge in the United States for which there are no approved medications for treatment. Vulnerability to environmental and drug-related cues previously associated with cocaine-taking behavior (“cue reactivity”) is thought to trigger cycles of dependence and relapse that contribute to high recidivism rates in cocaine use disorder. Thus an improved understanding of the mechanisms underlying cue reactivity is necessary to generate new pharmacotherapeutic strategies to prevent relapse in cocaine use disorder. Studies indicate that the agranular insular cortex (AIC) may play a key role in regulating cue reactivity by serving as a point of convergence for the interpretation of interoceptive signals and relay of this information to other nodes within corticostriatal circuitry. The excitatory and inhibitory balance in the AIC microcircuitry, maintained by resident glutamate projection neurons and γ-aminobutyric acid (GABA) interneurons, respectively, is critical to its normal function. Alterations in the excitatory/inhibitory balance in the cortex are hypothesized to drive processes engaged in drug seeking behavior in addiction. Serotonin (5-HT) neurotransmission through its cognate Gαq/11 protein-coupled 5-HT2C receptor (5-HT2CR) is important in maintaining cortical excitatory/inhibitory balance and in regulating cue reactivity, and these receptors are expressed in the AIC. We propose that one potential mechanism to suppress cue reactivity is through the harmonization of the functional connectivity in the AIC-corticostriatal circuit, controlled by the 5-HT2CR system within the AIC. Employing pharmacogenetic, biochemical, behavioral, genetic, and pharmacological methodologies, the present study will address this hypothesis through two Specific Aims: 1) interrogate the AIC corticostriatial circuity in cocaine cue reactivity, and 2) elucidate 5-HT2CR control of AIC over cue reactivity. The elucidation of the complex regulation of the 5-HT2CR modulation of the GABA:glutamate neuronal interaction within the AIC as it relates to cue reactivity will lead to a better understanding of individual risk factors for relapse in cocaine use disorder. This information will be utilized to inform therapeutic development for prevention of relapse to ultimately address this barrier in the treatment of cocaine use disorder.