Glutamate and prefrontal regulation of cocaine seeking after extinction

描述（由申请人提供）：吸毒成瘾的特征是强迫性地寻找和服用药物。这种强迫性是由环境因素引发的，而环境因素会随着药物暴露而成为条件反射。规范吸毒行为对预防吸毒复发至关重要。最简单的调节形式是消失，当强化物被忽略时，对刺激的条件反应就会减少。因此，在成瘾的情况下，当条件提示在没有药物奖励的情况下出现时，药物寻求会减少。消退学习通过形成抑制性记忆来减少觅药行为。人们普遍认为，消失是一种新的学习，像其他形式的学习一样，经历了习得、巩固和检索阶段。申请人和其他人之前进行的研究表明，内侧前额叶皮层（IL-mPFC）的边缘下区域在使用恐惧条件反射范式的消退巩固和恢复中起着关键作用。恐惧消退的巩固需要IL-mPFC中nmda受体的活性，无论是在消退期间还是之后。IL-mPFC是否也调节灭绝后的药物寻找行为才刚刚开始被破译。最近的研究表明IL-mPFC在药物寻找的消失中起作用，但这些研究主要集中在消失的表达上。关于IL-mPFC的可塑性及其在药物寻找消失中的作用尚不清楚。这项资助的总体目标是确定nmda受体介导的IL-mPFC的可塑性是否对可卡因寻求的消失的巩固是必要的。在目的1中，我们将评估IL-mPFC对可卡因寻求消退巩固的贡献，在消退的前三天使用训练前和训练后输注NMDA受体拮抗剂。在Aim 2中，我们将评估消除训练对IL-mPFC锥体神经元谷氨酸能突触传递的影响。这将通过在接受过灭绝训练的大鼠的前额叶切片上使用全细胞膜片钳记录来完成，以测量IL-mPFC神经元对附近刺激电极刺激的反应。我们将通过比较IL-mPFC神经元的反应，评估ampa受体和nmda受体介导的反应（EPSCs）在灭绝诱导下的变化，这些神经元来自接受过灭绝训练、未接受过灭绝训练或未接受过灭绝训练的大鼠。了解消失的神经机制可能会导致新的治疗方法，以提高基于消失的药物成瘾治疗的有效性。

DESCRIPTION (provided by applicant): Drug addiction is characterized by a compulsiveness to seek and take drugs. This compulsion is triggered by environmental cues that become conditioned with drug exposure. The regulation of drug seeking is imperative to the prevention of relapse. The simplest form of regulation is extinction, in which conditioned responding to a stimulus decreases when the reinforcer is omitted. Thus, in the case of addiction, drug seeking is reduced when conditioned cues are presented in the absence of the drug reward. Extinction learning reduces drug-seeking behavior through the formation of an inhibitory memory. It is generally accepted that extinction is new learning that, like other forms of learning, proceeds through acquisition, consolidation and retrieval phases. Studies performed previously by the applicant and others have demonstrated that the infralimbic region of the medial prefrontal cortex (IL-mPFC) plays a key role in the consolidation and retrieval of extinction using a fear conditioning paradigm. Consolidation of fear extinction requires NMDA-receptor activity in IL-mPFC, both during and after extinction. Whether IL-mPFC also regulates drug seeking behavior after extinction is only beginning to be deciphered. Recent work has implicated a role for IL-mPFC in extinction of drug seeking, but these studies focused on expression of extinction. Nothing is known about IL-mPFC plasticity or its role in extinction of drug seeking. The overall goal of this grant is to determine whether NMDA-receptor mediated plasticity in IL-mPFC is necessary for the consolidation of extinction of cocaine seeking. In Aim 1, we will evaluate the contribution of IL-mPFC to consolidation of extinction of cocaine seeking, using pre-training and post-training infusions of a NMDA receptor antagonist during the first three days of extinction. In Aim 2, we will evaluate the effect of extinction training on glutamatergic synaptic transmission in IL-mPFC pyramidal neurons. This will be done using whole cell patch-clamp recording in prefrontal slices of rats given extinction training, to measure the response of IL-mPFC neurons to stimulation by a nearby stimulating electrode. We will assess extinction-induced changes in AMPA-receptor- and NMDA-receptor- mediated responses (EPSCs) by comparing the responses of IL-mPFC neurons taken from rats that received either extinction training, no extinction, or were naive. Understanding the neural mechanisms of extinction could lead to new treatments to increase the effectiveness of extinction-based therapies for drug addiction. PUBLIC HEALTH RELEVANCE: Perhaps more than any other field in learning and memory, extinction is directly applicable to the treatment of various clinical disorders, which arise when conditioned responses are pathologically over-expressed. This research will explore the glutamatergic mechanisms of consolidation of extinction learning as it pertains to drug seeking. Understanding the mechanisms by which the prefrontal cortex consolidates extinction of drug seeking could lead to the development of pharmacotherapies to increase the effectiveness of extinction-based therapies for treatment of addiction.