Glucocorticoid-regulated endocannabinoids and stress-potentiated cocaine seeking

描述（由申请人提供）：尽管其流行，数十年的研究未能产生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，我们对促使戒断的可卡因成瘾者复发的情况和潜在的神经生物学过程的理解存在根本差距。众所周知，压力是导致药物复发的重要因素。考虑到其普遍和不可避免的性质，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，压力在复发中的作用比以前认为的要复杂得多，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给药/恢复的大鼠模型来检验压力在可卡因寻求中的“舞台设置”作用。使用该模型，我们已经证明，应激源（足电刺激）通过低于阈值的可卡因启动剂量促进恢复的能力需要皮质酮的增加和CB1R大麻素受体的激活。此外，我们的初步发现将这一机制定位于边缘皮层（PLC），这是谷氨酸能投射到伏隔核核心的来源，已被证明对可卡因使用至关重要。这一合作的多pi提案汇集了一个多学科的科学家团队，以测试假设，在压力下，皮质酮增强PLC中的内源性大麻素信号，从而抑制gaba能神经传递和解除对投射到伏隔核核心的锥体神经元的抑制。这种“舞台设置”机制允许低于阈值剂量的可卡因诱导恢复。该提案的目的1将研究应激诱导的内源性大麻素在PLC中增加的作用，重点是2-AG，以及CB1受体在应激诱导的可卡因寻求增强中的激活。目标2将调查的作用

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.