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 可卡因期间的神经适应和干预措施，可卡因的戒酒和干预措施 或海洛因自我给药以反向定义在触发前额叶皮层（PL）的前额叶皮层 随后寻求毒品。一个关键的问题是确定PL神经元的表型 激活并经历临界神经适应性，以便在禁欲期间扭转它们 并抑制继电器。为了实现这一目标，我们将使用特定途径的病毒载体和 可卡因或海洛因自我管理的戒酒期间的转基因技术以识别 PL神经元投射到伏隔核（NA）核心的PL神经元，这是对药物的缓解的基础 寻求。可卡因和海洛因对PL皮层的影响的关键特征是依赖营地 蛋白激酶A（PKA）引起AMPA谷氨酸受体的高磷酸化和 pcreb在禁欲的第一周。我们的初步数据表明这些 神经适应与PL的核突触过程的结构变化有关 PL锥体神经元的星形胶质细胞和锥体树突状刺，这些神经元投射到Na核心。 此外，我们的数据表明，这些更改可以通过管理 procysteine药物，N-乙酰半胱氨酸或PKA抑制剂RP-cAMPS，两者都会降低 复发到毒品。这些发现将通过测试以下来进一步研究 假设。 （1）可卡因和海洛因SA的禁欲将导致结构可塑性增加 与PL-NA核心神经元中可塑性相关的蛋白表达增强相关的 明确的D1或D2受体，这些变化将通过继电器与寻求药物的转移来逆转。 （2） 急性-PL PKA抑制作用或（3）在禁欲期间重复的全身性NAC注射 可卡因或海洛因SA将防止药物诱导的结构和突触可塑性变化。 此外，防止结构可塑性将与可塑性相关的降低有关 表达D1或D2受体并改善的PL-NA核心神经元中的蛋白质表达 复发到寻求毒品。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AS 以及PL-NA核心神经元和PL星形胶质细胞之间的相互作用，这些神经元可能提供新的 防止提示引起的可卡因和寻求海洛因的目标。