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: 10630231
• 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/10630231
• 关键词: AMPA Receptors; Abstinence; Acetylcysteine; Acute; Antioxidants; Astrocytes; CREB1 gene; Cocaine; Cocaine Dependence; Cues; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; 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; Rat Transgene; Rattus; Regulation; Relapse; Saline; Self Administration; Slice; Synapses; 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侧重于可卡因戒断期间的神经适应和干预 或海洛因自身给药以逆转触发前额叶皮质的前额叶皮质的缺陷 随后的毒品寻觅。一个关键的问题是确定PL神经元的表型 在戒酒期间被激活，并接受有利于复发的神经适应，以逆转它们 并抑制复发。为了实现这一目标，我们将使用路径特异性病毒载体和 转基因技术在可卡因或海洛因自我戒断过程中的鉴定 投射到伏核(NA)核心的PL神经元-药物复吸的基础- 寻找。可卡因和海洛因对PL皮质影响的一个关键特征是cAMP依赖 蛋白激酶A(PKA)导致AMPA谷氨酸受体过度磷酸化，并 PCREB在禁欲的第一周。我们的初步数据显示这些 神经适应与PL突触周围突起的结构变化有关 星形胶质细胞和投射到NA核心的PL锥体神经元的锥体树突棘。 此外，我们的数据表明，这些变化可以通过管理 原半胱氨酸药物N-乙酰半胱氨酸或PKA抑制剂RP-cAMP，两者均降低 又开始吸毒了。这些发现将通过测试以下内容来进一步调查 假设。(1)戒除可卡因和海洛因SA会导致结构可塑性增加 与PL-NA核心神经元可塑性相关蛋白表达增强有关 表达D1或D2受体，这些变化将被复发的药物寻求逆转。(2) 急性PL内PKA抑制或(3)戒断期间重复全身注射NAC。 可卡因或海洛因SA可防止药物引起的结构和突触可塑性的改变。 此外，防止结构塑性将与与塑性相关的减少有关 表达D_1或D_2受体并减少的PL-NA核心神经元蛋白表达 又开始吸毒了。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和结构/突触可塑性 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为新的 预防线索诱导的可卡因和寻求海洛因的目标。