Glucocorticoid-regulated endocannabinoids and stress-potentiated cocaine seeking

描述（由申请人提供）：尽管它的流行，几十年的研究未能产生FDA批准的药物用于治疗可卡因成瘾。缺乏可行的药理学方法，部分原因是我们对促使戒除可卡因成瘾者复吸的情况和潜在神经生物学过程的理解存在根本性差距。众所周知，压力是药物复吸的一个重要因素。考虑到其普遍性和不可避免的性质，压力和吸毒之间的这种关系是非常有问题的。最近的研究结果表明，压力在复吸中的作用比人们曾经认为的要复杂得多，压力不仅会引发可卡因的使用，而且会通过提高对与毒品有关的刺激的敏感性而间接促进毒品复吸。我们的团队已经建立了一个自我管理/恢复大鼠模型，以检查这种“阶段设置”的作用，在可卡因寻求压力。使用这个模型，我们已经证明，一个应激源（电脚电击），以促进恢复，否则阈下启动剂量的可卡因需要增加皮质酮和CB 1 R大麻素受体的激活的能力。此外，我们的初步研究结果已经将这种机制定位于前边缘皮层（PLC），这是一个向神经核投射神经元的来源，已被证明对可卡因的使用至关重要。这个合作的多PI提案汇集了一个多学科的科学家团队来测试假设，即在应激期间，皮质酮增强PLC中的内源性大麻素信号传导，从而抑制GABA能神经传递并解除抑制投射到核内的锥体神经元。这种“阶段设定”机制允许阈下剂量的可卡因诱导复吸。该提案的目的1将研究压力诱导的内源性大麻素增加在PLC中的作用，重点是2-AG，以及由此产生的CB 1受体在可卡因寻求的压力诱导的增强中的激活。目标2将研究 皮质酮调节内源性大麻素信号在PLC中的可卡因寻求和这种调节发生的机制的压力的影响。该提案的目标3将研究PLC中这些应激诱导的改变如何破坏投射到延髓核核心以促进可卡因使用的锥体神经元的GABA能调节。这些拟议实验的结果有可能导致开发新的和更有效的治疗方法来管理可卡因成瘾。然而，确定压力改变大脑皮层对这一通路的调节的机制的重要性不仅限于成瘾，而且应该指导我们理解压力如何调节一般的动机行为，从而如何导致一系列神经精神疾病。

DESCRIPTION (provided by applicant): Despite its prevalence, decades of research have failed to yield an FDA-approved medication for the treatment of cocaine addiction. The lack of viable pharmacotherapeutic approaches is attributable, in part, to fundamental gaps in our understanding of the situations and underlying neurobiological processes that promote relapse to drug use in abstinent cocaine addicts. It is well established that stress is an important contributor to drug relapse. Considering its pervasive and unavoidable nature, this relationship between stress and drug use is highly problematic. Recent findings indicate that the role of stress in relapse is more complex than once believed and that, rather than simply triggering cocaine use, stress can indirectly promote drug relapse by heightening sensitivity to drug-associated stimuli. Our team has established a self-administration/reinstatement rat model for examining this "stage-setting" role for stress in cocaine seeking. Using this model, we have demonstrated that the ability of a stressor (electric foot shock) to promote reinstatement by an otherwise subthreshold priming dose of cocaine requires increases in corticosterone and activation of CB1R cannabinoid receptors. Moreover, our preliminary findings have localized this mechanism to the prelimbic cortex (PLC), a source of glutamatergic projections to the nucleus accumbens core that have been shown to be critical for cocaine use. This collaborative multi-PI proposal brings together a multi-disciplinary team of scientists to test the hypothesis that, durin stress, corticosterone enhance endocannabinoid signaling in the PLC, thereby suppressing GABAergic neurotransmission and disinhibiting pyramidal neurons that project to the nucleus accumbens core. This "stage- setting" mechanism allows for subthreshold doses of cocaine to induce reinstatement. Aim 1 of the proposal will examine the role of stress-induced increases in endocannabinoids in the PLC, with a focus on 2-AG, and the resulting activation of CB1 receptors in the stress-induced potentiation of cocaine seeking. Aim 2 will investigate the role of corticosterone regulation of endocannabinoid signaling in the PLC in the effects of stress on cocaine seeking and the mechanisms through which this regulation occurs. Aim 3 of the proposal will examine how these stress-induced alterations in the PLC disrupt GABAergic regulation of pyramidal neurons that project to the nucleus accumbens core to promote cocaine use. The findings from these proposed experiments have the potential to lead to the development of new and more effective treatment approaches for the management of cocaine addiction. However, the importance of defining the mechanisms through which stress alters cortical regulation of this pathway extends beyond addiction and should guide our understanding of how stress regulates motivated behavior in general and therefore how it contributes to a range of neuropsychiatric conditions.