Prevention of Cocaine-induced Prefrontal ERK Shutoff During Early Withdrawal

描述（由申请人提供）：该申请将确定在可卡因自我给药（SA）早期戒断期间引发持续可卡因寻求的ERK MAP激酶和背内侧前额叶皮质（PFC）深度去磷酸化的机制。我们已经证明，PFC的ERK去磷酸化（或“关闭”）发生在重复每日可卡因SA结束后的2小时内。单次向PFC注入脑源性神经营养因子（BDNF）逆转ERK关闭，可使伏隔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不是一种有用的治疗药物，因为它是一种神经肽，不能有效地穿过血脑屏障。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点。我们提出了一个基本原理和初步证据来支持ERK关闭是由GluN2B受体激活ERK磷酸酶STEP介导的假设。我们建议从以下几个方面来研究这一假设。在Aim 1中，我们将研究早期戒断可卡因SA时ERK磷酸酶激活、NMDA受体表面表达和突触/突触外分布的变化。在Aim 2中，我们将研究GluN2A或GluN2B受体拮抗剂是否会在戒断和戒毒训练后的早期戒断和持续可卡因寻求期间抑制PFC中可卡因诱导的ERK/CREB关闭。在Aim 3中，我们将研究钙调磷酸酶和ERK磷酸酶（STEP或蛋白磷酸酶2A）的抑制是否会逆转早期戒断期间可卡因诱导的ERK/CREB关闭，并抑制戒断和戒毒训练后的可卡因寻求。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药物寻求复发的关键神经生物学底物的理解，从而影响药物滥用研究领域，并有可能在早期戒断期间产生新的预防干预措施。

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.