COCA - Project 2 Preventing Drug-induced Neuroadaptations in Prelimbic Cortex

COCA - 项目 2 预防前边缘皮层药物诱导的神经适应

• 批准号: 10404585
• 负责人: Jacqueline F. McGinty
• 金额: $ 24.92万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404585
• 关键词: AMPA Receptors; Abstinence; Acetylcysteine; Acute; Antioxidants; Astrocytes; CREB1 gene; Cocaine; Cocaine Dependence; Cues; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cysteine; Data; Dendritic Spines; Dopamine D1 Receptor; Dopamine D2 Receptor; Excitatory Synapse; Glutamate Receptor; Glutamates; Goals; Heroin; Infusion procedures; Injections; Intervention; Mediating; Morphology; N-Methylaspartate; Neurons; Nuclear; Nucleus Accumbens; Opiate Addiction; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physiologic pulse; Prefrontal Cortex; Process; Procysteine; Protein Kinase A Inhibitor; Proteins; Rattus; Regulation; Relapse; Saline; Self Administration; Slice; Synaptic plasticity; Technology; Testing; Transgenic Organisms; Viral Vector; cocaine self-administration; hippocampal pyramidal neuron; immunoreactivity; neuroadaptation; prevent; protein expression; receptor expression; selective expression

PROJECT SUMMARY – Project 2 COCA Project 2 focuses on neuroadaptations and interventions during abstinence from cocaine or heroin self-administration to reverse deficits in the prelimbic (PL) prefrontal cortex that trigger subsequent drug-seeking. A critical issue is to identify the phenotype of the PL neurons that are activated and undergo pro-relapse neuroadaptations in order to reverse them during abstinence and suppress relapse. To accomplish this goal, we will use pathway-specific viral vector and transgenic technology during abstinence from cocaine or heroin self-administration to identify PL neurons projecting to the nucleus accumbens (NA) core that underlie relapse to drug- seeking. A critical feature of cocaine’s and heroin’s effects on PL cortex is that cAMP-dependent protein kinase A (PKA) causes hyper-phosphorylation of AMPA glutamate receptors and pCREB during the first week of abstinence. Our preliminary data indicate that these neuroadaptations are associated with structural changes in perisynaptic processes of PL astrocytes and pyramidal dendritic spines of PL pyramidal neurons that project to the NA core. Further, our data indicate that these changes can be reversed by administration of the procysteine drug, N-acetylcysteine, or the PKA inhibitor, Rp-cAMPs, both of which decrease relapse to drug seeking. These findings will be further investigated by testing the following hypotheses. (1) Abstinence from cocaine and heroin SA will cause increased structural plasticity associated with enhanced plasticity-related protein expression in PL-NA core neurons that express D1 or D2 receptors and these changes will be reversed by relapse to drug seeking. (2) Acute intra-PL PKA inhibition or (3) repeated, systemic NAC injections during abstinence from cocaine or heroin SA will prevent the drug-induced changes in structural and synaptic plasticity. Moreover, preventing structural plasticity will be associated with a decrease in plasticity-related protein expression in PL-NA core neurons that express D1 or D2 receptors and decreased relapse to drug-seeking. This project will discover new relationships between key plasticity- related proteins and structural/synaptic plasticity in a subpopulation of PL-NA core neurons, as well as interactions between PL-NA core neurons and PL astrocytes that may provide new targets for preventing cue-induced cocaine and heroin-seeking.

项目摘要 – 项目 2 COCA 项目 2 重点关注可卡因戒断期间的神经适应和干预 或海洛因自我给药，以逆转前边缘（PL）前额皮质的缺陷，从而触发 随后的药物寻找的一个关键问题是确定 PL 神经元的表型。 激活并经历促复发神经适应，以便在禁欲期间逆转它们 为了实现这一目标，我们将使用途径特异性病毒载体和 转基因技术在戒除可卡因或海洛因自我管理期间识别 PL 神经元投射到伏隔核 (NA) 核心，这是药物复发的基础 可卡因和海洛因对 PL 皮质的影响的一个关键特征是 cAMP 依赖性。 蛋白激酶 A (PKA) 导致 AMPA 谷氨酸受体过度磷酸化， 我们的初步数据表明，禁欲第一周期间的 pCREB。 神经适应与 PL 突触周围过程的结构变化相关 星形胶质细胞和 PL 锥体神经元的锥体树突棘投射到 NA 核心。 此外，我们的数据表明，这些变化可以通过管理来逆转 原半胱氨酸药物 N-乙酰半胱氨酸或 PKA 抑制剂 Rp-cAMPs，两者都会降低 将通过测试以下内容进一步调查这些发现。 (1)戒除可卡因和海洛因SA会导致结构可塑性增加 与 PL-NA 核心神经元中可塑性相关蛋白表达增强相关 表达 D1 或 D2 受体，这些变化将因寻求药物复发而逆转 (2)。 急性 PL 内 PKA 抑制或 (3) 戒断期间重复全身性 NAC 注射 可卡因或海洛因 SA 会阻止药物引起的结构和突触可塑性变化。 此外，防止结构塑性将与塑性相关的减少有关。 表达 D1 或 D2 受体的 PL-NA 核心神经元中的蛋白质表达减少 该项目将发现关键可塑性之间的新关系。 PL-NA 核心神经元亚群中的相关蛋白质和结构/突触可塑性，如 以及 PL-NA 核心神经元和 PL 星形胶质细胞之间的相互作用，可能提供新的 防止因线索诱发可卡因和海洛因寻求的目标。