Glucocorticoid-regulated endocannabinoids and stress-potentiated cocaine seeking

糖皮质激素调节的内源性大麻素和压力增强的可卡因寻求

基本信息

批准号：
9053466
负责人：
Cecilia J Hillard
金额：
$ 43.36万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9053466
关键词：
2-arachidonylglycerol Affect Behavior CNR1 gene Chemosensitization Cocaine Cocaine Dependence Complex Corticosterone Cues Development Dose Drug usage Endocannabinoids FDA approved Figs - dietary Glucocorticoid Receptor Glucocorticoids Glutamates Goals Health Injection of therapeutic agent Interneurons Lead Mediating Medical Modeling Myoepithelial cell Nature Neurobiology Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Play Predisposition Prefrontal Cortex Prevalence Process Production Public Health Rattus Receptor Activation Regulation Relapse Research Role Scheme Scientist Self Administration Shock Site Societies Source Staging Stimulus Stress Testing addiction cannabinoid receptor cell type cocaine use cost craving disorder later incidence prevention drug relapse effective therapy endocannabinoid signaling foot gamma-Aminobutyric Acid hippocampal pyramidal neuron motivated behavior neuropsychiatry neurotransmission novel prevent research study response stressor

项目摘要

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.

描述（由申请人提供）：尽管普遍存在，数十年的研究未能产生FDA批准的药物来治疗可卡因成瘾。缺乏可行的药物治疗方法的部分原因是我们理解和潜在的神经生物学过程的基本差距，这些过程促进了可卡因成瘾者中促进药物使用的复发。众所周知，压力是药物复发的重要原因。考虑到其普遍性和不可避免的性质，压力与吸毒之间的这种关系是高度问题的。最近的发现表明，压力在复发中的作用比一旦相信的更为复杂，而不是简单地触发可卡因的使用，而是通过提高对药物相关刺激的敏感性而间接促进药物复发。我们的团队已经建立了一个自我管理/恢复大鼠模型，用于检查可卡因寻求可卡因的“阶段设定”角色。使用该模型，我们已经证明了应激源（电脚冲击）通过其他亚阈值启动剂量可卡因促进恢复原状的能力，需要增加皮质酮和激活CB1R大麻素受体的能力。此外，我们的初步发现将此机制定位于前比皮层（PLC），这是对牙核胃核心核心的谷氨酸能投影的来源，已被证明对可卡因使用至关重要。该协作的多PI-PI提案汇集了一个多学科的科学家团队，以检验以下假设：杜林压力，皮质酮可增强PLC中的内源性大麻素信号传导，从而抑制GABA能神经传递并抑制抑制锥体神经元，从而向核核生物核心核心核心。这种“阶段设置”机制允许可卡因的亚阈值剂量诱导恢复原状。该提案的目标1将检查plc中内源性大麻素的增加的作用，重点是2-AG，以及由CB1受体的激活在应力诱导的可卡因寻求增强中的激活。 AIM 2将调查 plc中内源性大麻素信号传导对可卡因寻求可卡因的影响和这种调节发生的机制的影响。该提案的AIM 3将研究这些应力诱导的PLC中的变化如何破坏锥体神经元的GABA能调节，这些神经元将其投射到伏伏核核心以促进可卡因的使用。这些提出的实验的发现有可能导致开发可卡因成瘾的新的，更有效的治疗方法。但是，定义压力改变该途径的皮质调节的机制的重要性超出了成瘾的范围，并应指导我们对压力如何调节积极行为的理解，从而导致其如何促进一系列神经精神疾病。