Glucocorticoid-regulated endocannabinoids and stress-potentiated cocaine seeking

描述(申请人提供)：尽管可卡因成瘾率很高，但几十年的研究都未能产生FDA批准的治疗可卡因成瘾的药物。缺乏可行的药物治疗方法的部分原因是，我们对促使戒除可卡因成瘾者复发的情况和潜在的神经生物学过程的了解存在根本差距。众所周知，压力是导致药物复发的一个重要因素。考虑到它的普遍和不可避免的性质，这种压力和药物使用之间的关系是非常有问题的。最近的研究结果表明，压力在复发中的作用比人们曾经认为的要复杂得多，而且压力不是简单地引发可卡因的使用，而是通过提高对药物相关刺激的敏感性来间接促进药物复发。我们的团队已经建立了一个自我管理/恢复状态的大鼠模型，用于研究压力在寻求可卡因过程中的这种“舞台设定”作用。使用这个模型，我们已经证明了应激源(足部电击)通过其他亚阈值激发剂量的可卡因促进恢复的能力需要皮质酮的增加和CB1R大麻受体的激活。此外，我们的初步发现将这一机制定位于初级皮质(PLC)，这是到伏隔核核心的谷氨酸能投射的来源，已被证明是可卡因使用的关键。这一协作的多PI提案汇集了一个多学科的科学家团队来测试这一假设，即在持续应激时，皮质酮增强PLC中的内源性大麻信号，从而抑制GABA能神经传递，并抑制投射到伏隔核核心的锥体神经元。这种“舞台设定”机制允许亚阈值剂量的可卡因诱导恢复。该提案的目的1将研究应激诱导PLC中内源性大麻素增加的作用，重点是2-AG，以及由此导致的CB1受体在应激诱导的可卡因寻求增强中的激活。目标2将调查 皮质酮对PLC中内源性大麻素信号的调节应激对可卡因寻找的影响及其调节发生的机制。该提案的目的3将研究PLC中这些应激诱导的变化如何扰乱锥体神经元的GABA能调节，这些锥体神经元投射到伏隔核核心以促进可卡因的使用。这些拟议实验的发现有可能导致开发新的、更有效的治疗方法来管理可卡因成瘾。然而，定义压力改变这一途径的皮质调节机制的重要性不仅限于成瘾，而且应该指导我们理解应激如何调节一般的动机行为，从而如何促进一系列神经精神疾病的发生。

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.