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.

项目概要-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 或海洛因自我管理，以扭转前边缘（PL）前额皮质的缺陷， 随后的药物寻找。一个关键的问题是确定PL神经元的表型， 激活并经历复发前的神经适应，以便在禁欲期间逆转它们 抑制复发为了实现这一目标，我们将使用途径特异性病毒载体， 在可卡因或海洛因自我给药戒断期间使用转基因技术， PL神经元投射到延髓核（NA）核心，是药物复发的基础。 寻找可卡因和海洛因对PL皮层作用的一个关键特征是cAMP依赖性的 蛋白激酶A（PKA）引起AMPA谷氨酸受体的过度磷酸化， pCREB在禁欲的第一周。我们的初步数据显示， 神经适应与PL突触周过程的结构变化有关 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，这些变化可以通过给予 前半胱氨酸药物，N-乙酰半胱氨酸，或PKA抑制剂，Rp-cAMPs，两者都降低 重新吸毒这些发现将通过测试以下内容进行进一步调查 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核心神经元中可塑性相关蛋白表达增强相关， 表达D1或D2受体，并且这些变化将通过药物寻求的复发而逆转。（二） 急性PL内PKA抑制或（3）戒断期间重复全身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的变化。 此外，阻止结构塑性将与塑性相关的降低有关。 在表达D1或D2受体的PL-NA核心神经元中的蛋白表达降低， 重新吸毒这个项目将发现关键可塑性之间的新关系- 相关蛋白质和结构/突触可塑性在一个亚群的PL-NA核心神经元， 以及PL-NA核心神经元和PL星形胶质细胞之间的相互作用， 防止线索诱导的可卡因和海洛因寻找的目标。