Effects of Chronic Opiates on Endocannabinoid Signaling at Excitatory Synapses

慢性阿片类药物对兴奋性突触内源性大麻素信号传导的影响

• 批准号: 7612861
• 负责人: Stanley A Thayer
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612861
• 关键词: Abstinence; Affect; Agonist; Behavioral; Brain-Derived Neurotrophic Factor; CNR1 gene; Cannabinoids; Chronic; Cultured Cells; Data; Development; Diffuse; Disinhibition; Drug Addiction; Elements; Endocannabinoids; Excision; Excitatory Synapse; Exposure to; Funding; Hippocampus (Brain); Link; Mediating; Modeling; Morphine; Neurons; Opiate Addiction; Opiates; Opioid; Personal Satisfaction; Pharmaceutical Preparations; Production; Receptor Up-Regulation; Secondary to; Signal Transduction; Stimulus; Synapses; Synaptic Transmission; System; Testing; Withdrawal; base; direct application; drug of abuse; gamma-Aminobutyric Acid; in vitro Model; insight; neuroadaptation; neurotransmission; neurotransmitter release; postsynaptic; presynaptic; receptor; receptor sensitivity

The endocannabinoid (eCB) system participates in behavioral adaptations that accompany chronic exposure to opiates; the cellular bases for these changes are not known. One form of eCB signaling involves the postsynaptic production of eCBs that diffuse in a retrograde manner to act on presynaptic CB1 receptors to inhibit neurotransmitter release. In the prior funding period a cell culture model that displays robust eCBmediated depolarization-induced suppression of excitatory synaptic transmission (DSE) was developed. Preliminary data show that this model is well suited for examining adaptive changes in retrograde eCB signaling between hippocampal neurons. Three specific aims will examine the effects of prolonged exposure to opiates on the eCB system. 1) Opiates exert marked effects on synaptic transmission between hippocampal neurons. The hypothesis that prolonged exposure to opiates will up-regulate eCB signaling will be tested. 2) Chronic exposure to opiate agonists increases the expression of brain derived neurotrophic factor (BDNF) and increases excitatory synaptic transmission. The hypothesis that BDNF and intense synaptic activity will produce a long-lasting strengthening of the eCB system will be tested. 3) CB1 antagonists show promise for the treatment of opiate addiction. How prolonged CB1 receptor blockade affects the function of the eCB system is not known. The hypothesis that removal of a CB1 receptor antagonist following prolonged blockade of presynaptic CB1 receptors will result in enhanced endocannabinoid signaling will be tested. Overall, these studies will provide insight into whether the pre- and post-synaptic elements of the eCB system change in parallel during exposure to and withdrawal from opiates. Understanding the plasticity of the system as a whole will aid in developing agents to modulate eCB signaling during withdrawal and abstinence from opiates.

内源性大麻素 (eCB) 系统参与伴随长期暴露的行为适应 阿片类药物；这些变化的细胞基础尚不清楚。 eCB 信令的一种形式涉及 突触后产生的 eCB 以逆行方式扩散，作用于突触前 CB1 受体 抑制神经递质释放。在之前的资助期间，细胞培养模型表现出强大的 eCB 介导 开发了去极化诱导的兴奋性突触传递抑制（DSE）。 初步数据表明，该模型非常适合检查逆行 eCB 的适应性变化 海马神经元之间的信号传导。三个具体目标将研究长期暴露的影响 ECB 系统上的阿片类药物。 1）阿片类药物对神经元之间的突触传递有显着影响 海马神经元。长期接触阿片类药物会上调 eCB 信号传导的假设将 被测试。 2) 长期接触阿片激动剂会增加脑源性神经营养因子的表达 因子（BDNF）并增加兴奋性突触传递。 BDNF 和强烈的假设 突触活动将产生持久的增强，eCB 系统将受到测试。 3）CB1 拮抗剂显示出治疗阿片成瘾的希望。 CB1受体阻断多长时间 影响 eCB 系统功能尚不清楚。去除 CB1 受体的假设 长期阻断突触前 CB1 受体后拮抗剂将导致增强 将测试内源性大麻素信号传导。总体而言，这些研究将深入了解预和 在接触和退出过程中，eCB 系统的突触后元件会并行变化。 阿片类药物。了解整个系统的可塑性将有助于开发调节 eCB 的试剂 在阿片类药物戒断和戒断过程中发出信号。