Prevention of Cocaine-induced Prefrontal ERK Shutoff During Early Withdrawal

描述（由申请人提供）：本申请将确定在可卡因自我给药（SA）早期戒断期间ERK MAP激酶和背内侧前额叶皮层（PFC）中深度去磷酸化的潜在机制，这些机制触发持续的可卡因寻求。我们已经证明，ERK去磷酸化（或“关闭”）在PFC发生在2小时内结束的重复，每天可卡因SA。通过将脑源性神经营养因子（BDNF）单次输注到PFC中来逆转ERK关闭，使延髓核中的谷氨酸传递正常化，并抑制戒断动物长达三周的可卡因寻求。然而，BDNF不是一种治疗上有用的药物，因为它是一种不能有效穿过血脑屏障的神经肽。因此，有必要对可卡因SA诱导的ERK关闭的分子机制进行表征，以确定药物开发的替代靶点。我们提出了一个基本原理和初步的证据来支持这一假设，ERK关闭介导的GluN 2B受体激活的ERK磷酸酶，STEP。我们建议在以下目标中研究这一假设。在目的1中，我们将调查的变化，ERK磷酸酶激活和表面表达和突触/突触外分布的NMDA受体早期退出可卡因SA。在目标2中，我们将研究GluN 2A或GluN 2B受体拮抗剂是否会抑制可卡因诱导的ERK/CREB关闭PFC在早期戒断和持续可卡因寻求后，禁欲和灭绝训练。在目标3中，我们将研究是否抑制钙调神经磷酸酶和ERK磷酸酶，STEP或蛋白磷酸酶2A，将逆转可卡因诱导的ERK/CREB关闭在早期戒断和抑制可卡因寻求戒断和消退训练后。这些研究将影响药物滥用研究领域，通过推进我们对介导可卡因诱导的神经适应和药物寻求复发的关键神经生物学底物的理解，并有可能在早期戒断期间采取新的预防性干预措施。

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.