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(申请人提供)：这项申请将确定在可卡因自我给药(SA)早期戒断过程中ERK MAP激酶和背内侧前额叶皮质(PFC)深刻去磷酸化的潜在机制，这会引发持续的可卡因寻找。我们已经证明，PFC中ERK去磷酸化(或“关闭”)发生在重复的每日可卡因SA结束后2小时内。通过向PFC注入一次脑源性神经营养因子(BDNF)来逆转ERK的关闭，可以使伏隔核中的谷氨酸传递正常化，并在长达三周的时间内抑制戒断动物的可卡因寻求。然而，BDNF不是一种治疗有用的药物，因为它是一种神经肽，不能有效地穿越血脑屏障。因此，有必要对可卡因SA诱导的ERK阻断的分子机制进行表征，以确定药物开发的替代靶点。我们提供了一个理论基础和初步证据来支持ERK关闭是由ERK磷酸酶STEP的GluN2B受体激活所介导的假设。我们建议从以下几个方面来研究这一假说。在目标1中，我们将研究可卡因SA戒断早期ERK磷酸酶活性、NMDA受体的表面表达和突触/突触外分布的变化。在目标2中，我们将研究GluN2A或GluN2B受体拮抗剂是否能抑制可卡因诱导的ERK/CREB在早期戒断和戒断训练后持续寻找可卡因的PFC中的关闭。在目标3中，我们将研究抑制钙调神经磷酸酶和ERK磷酸酶(STEP或蛋白磷酸酶2A)是否能逆转可卡因诱导的ERK/CREB在早期戒断过程中的关闭，并抑制戒断和消退训练后的可卡因寻找。这些研究将通过促进我们对介导可卡因诱导的神经适应和对寻求药物的复发的关键神经生物学底物的了解来影响药物滥用研究领域，并有可能在早期戒断期间导致新的预防干预措施。