Effects of Chronic Opiates on Endocannabinoid Signaling at Excitatory Synapses

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。eCB信号传导的一种形式涉及 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。在之前的资助期内，细胞培养模型显示出稳定的eCB介导的 开发了去极化诱导的兴奋性突触传递（DSE）抑制。 初步数据表明，该模型非常适合于检查逆行eCB的适应性变化， 海马神经元之间的信号传递。三个具体的目标将检查长期暴露的影响 和鸦片类药物的混合物1)阿片类药物对突触传递有显著影响， 海马神经元假设长期暴露于阿片类药物会上调eCB信号传导， 得到考验2)慢性阿片受体激动剂暴露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。假设BDNF和强烈的 突触活动将产生持久的eCB系统的加强将被测试。3)CB1 拮抗剂显示出治疗阿片成瘾的希望。如何延长CB1受体阻滞剂 影响eCB系统的功能尚不清楚。一种假说认为，去除CB1受体 拮抗剂后，突触前CB1受体的长期封锁将导致增强 将测试内源性大麻素信号传导。总的来说，这些研究将提供洞察力， eCB系统的突触后元件在暴露于和退出期间平行变化。 鸦片类药物了解整个系统的可塑性将有助于开发调节eCB的药物 在戒断和戒除鸦片时发出信号。

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.