Prevention of Cocaine-induced Prefrontal ERK Shutoff During Early Withdrawal

早期戒断期间预防可卡因引起的前额叶 ERK 关闭

• 批准号: 8439031
• 负责人: Jacqueline F. McGinty
• 金额: $ 31.26万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439031
• 关键词: Abstinence; Animals; Attention; Blood - brain barrier anatomy; Brain-Derived Neurotrophic Factor; CREB1 gene; Calcineurin; Calcineurin inhibitor; Chimeric Proteins; Cocaine; Cocaine Dependence; Corpus striatum structure; Cues; Cyclosporine; Data; Development; Drug abuse; Event; Extinction (Psychology); Extracellular Signal Regulated Kinases; Glutamate Receptor; Glutamates; Homebound Persons; Infusion procedures; Intervention; Knowledge; Lead; MAP Kinase Modules; Measures; Mediating; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Neurobiology; Neuropeptides; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Pre-Clinical Model; Prefrontal Cortex; Preventive Intervention; Protein Dephosphorylation; Protein phosphatase; Rattus; Receptor Activation; Recording of previous events; Regulation; Relapse; Research; Self Administration; Self-Administered; Surface; Synapses; Training; Withdrawal; addiction; cocaine prevention; extracellular; in vivo Model; inhibitor/antagonist; neuroadaptation; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; prevent; public health relevance; receptor; relating to nervous system; transmission process

DESCRIPTION (provided by applicant): This application will determine the mechanisms underlying a profound dephosphorylation of ERK MAP kinase and in the dorsomedial prefrontal cortex (PFC) during early withdrawal from cocaine self-administration (SA) that trigger persistent cocaine-seeking. We have demonstrated that ERK dephosphorylation (or "shutoff") in the PFC occurs within 2 hr of the end of repeated, daily cocaine SA. Reversing the ERK shutoff with a single infusion of brain-derived neurotrophic factor (BDNF) into the PFC normalizes glutamate transmission in the nucleus accumbens and suppresses cocaine-seeking in abstinent animals for as long as three weeks. However, BDNF is not a therapeutically useful medication because it is a neuropeptide that does not effectively cross the blood-brain barrier. Therefore, it is necessary to characterize the molecular mechanisms underlying the cocaine SA-induced ERK shutoff in order to identify alternative targets for medication development. We present a rationale and preliminary evidence to support the hypothesize that the ERK shutoff is mediated by GluN2B receptor activation of the ERK phosphatase, STEP. We propose to investigate this hypothesis in the following aims. In Aim 1, we will investigate changes in ERK phosphatase activation and the surface expression and synaptic/extrasynaptic distribution of NMDA receptors during early withdrawal from cocaine SA. In Aim 2, we will investigate whether antagonists of GluN2A or GluN2B receptors will suppress the cocaine-induced ERK/CREB shut-off in the PFC during early withdrawal and persistent cocaine-seeking after abstinence and extinction training. In Aim 3, we will investigate whether or not inhibition of calcineurin and the ERK phosphatases, STEP or protein phosphatase 2A, will reverse the cocaine-induced ERK/CREB shut-off during early withdrawal and suppress cocaine-seeking after abstinence and extinction training. These studies will impact the field of drug abuse research by advancing our understanding of the key neurobiological substrates that mediate cocaine-induced neuroadaptations and relapse to drug-seeking with the potential of leading to novel preventive interventions during early withdrawal.

描述（由申请人提供）：本申请将确定ERK MAP激酶的深刻去磷酸化的机制以及在早期从可卡因自我给药（SA）提早撤离期间触发可卡因可卡因的可卡因时，在背膜前额叶皮层（PFC）中。我们已经证明，PFC中的ERK去磷酸化（或“关闭”）发生在重复的每日可卡因SA结束的2小时内。将ERK关闭逆转，单次输注大脑衍生的神经营养因子（BDNF）中的PFC使伏隔核中的谷氨酸传播归一化，并抑制了避免动物中可卡因的可卡因长达三周。但是，BDNF不是一种治疗用药，因为它是一种神经肽，无法有效地穿越血脑屏障。因此，有必要表征可卡因SA诱导的ERK关闭的分子机制，以确定药物开发的替代靶标。我们提出了一个基本原理和初步证据，以支持假设ERK关闭是由ERK磷酸酶的Glun2b受体激活介导的。我们建议在以下目的中研究这一假设。在AIM 1中，我们将研究ERK磷酸酶激活的变化以及NMDA受体从可卡因SA提早退出期间的表面表达和突触/突触外分布。在AIM 2中，我们将研究Glun2a或Glun2b受体的拮抗剂是否会在早期撤离和持续的可卡因寻求和灭绝训练后抑制PFC中可卡因诱导的ERK/CREB关闭。在AIM 3中，我们将调查抑制钙调神经蛋白酶和ERK磷酸酶，步骤或蛋白质磷酸酶2a是否会逆转可卡因诱导的ERK/CREB在早期撤离期间的关闭，并在戒烟和灭绝训练后抑制可卡因寻求可卡因。这些研究将通过促进我们对介导可卡因诱导的神经适应的关键神经生物学底物的理解来影响药物滥用研究领域，并可能在早期戒断期间进行新的预防干预措施，从而可能导致新的预防干预措施。