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)系统参与伴随慢性暴露的行为适应 阿片类药物；这些变化的细胞基础尚不清楚。欧洲央行信号的一种形式涉及 以逆行方式扩散的ECB在突触后产生作用于突触前CB1受体 抑制神经递质的释放。在之前的资助期，细胞培养模型显示了强大的eCBi中介 去极化抑制兴奋性突触传递(DSE)的研究进展。 初步数据显示，该模型非常适合考察欧洲央行逆行的适应性变化 海马神经元之间的信号传递。三个具体目标将检验长时间暴露的影响。 欧洲央行系统上的鸦片类药物。1)阿片类药物对突触传递有显著影响。 海马神经元。长期接触阿片类药物将上调欧洲央行信号的假说将 接受测试。2)长期接触阿片类激动剂可增加脑源性神经营养因子的表达 脑源性神经营养因子(BDNF)并增加兴奋性突触传递。假设脑源性神经营养因子和强神经营养因子 突触活动是否会产生持久的欧洲央行系统的加强将受到考验。3)CB1 拮抗剂显示出治疗鸦片成瘾的希望。如何延长CB1受体的阻断时间 影响欧洲央行系统的功能尚不清楚。移除CB1受体的假说 长时间阻断突触前CB1受体后的拮抗剂将导致增强 将测试内源性大麻素信号。总体而言，这些研究将提供洞察，以了解是否前和 在暴露和退出期间，欧洲央行系统的突触后元素平行变化 鸦片类药物。了解整个系统的可塑性将有助于开发调节欧洲央行的因素 戒断和阿片类药物戒断期间的信号。