GABAergic Sensitization of the Serotonin System in Stress-Induced Opiate Relapse

描述（由申请人提供）：阿片类药物是有效的镇痛药，但也有很高的滥用风险。即使在长期戒断后，前阿片类药物成瘾者仍然容易复发，特别是在压力条件下。大多数对阿片类药物成瘾和复发机制的关注都集中在传统的多巴胺能奖励途径上。很少有研究检查5-羟色胺（5-羟色胺；5-HT）系统在阿片类药物成瘾和复发中的作用。啮齿类动物的初步数据表明，应激与阿片历史相互作用，使5-HT中隔背核（DRN）神经元对gaba能抑制敏感。最近的研究发现了DRN中GABA信号与应激诱导的阿片类药物恢复之间的因果关系。我们假设这种氨基丁酸能致敏导致血清素能功能低下和随之而来的不安情绪状态，从而驱动药物寻求行为，从而使压力诱导的阿片类药物复发易感性。在当前的应用中，我们将采用两种最先进的基因突变策略，使用Cre-loxP系统来设计选择性地在DRN或特异性地在5-HT神经元中缺乏GABAA受体的小鼠。首先，我们将利用免疫组织化学、电生理和定量放射自显影技术确认这些小鼠中GABAA受体的DRN或5- ht特异性缺失。接下来，我们将在两种互补的复发动物模型中测试这些小鼠，其中游泳压力用于恢复先前消失的吗啡条件下的位置偏好或自我给药。我们预测，在应激诱导的复发模型中，这些小鼠将免受5-HT DRN系统中观察到的gaba能致敏，因此在这两种模型中不太容易复发。这些研究将产生阿片类药物复发抵抗的创新动物模型，这将是阐明导致阿片类药物复发的5-HT DRN系统内新回路的有价值的工具。这种方法可以确定治疗阿片成瘾和预防复发的新靶点。

DESCRIPTION (provided by applicant): Opioids are effective analgesics but also carry a high abuse liability. Even after prolonged abstinence, former opioid addicts can remain vulnerable to relapse, particularly under stressful conditions. Most of the focus on opioid addiction and relapse mechanisms have centered on traditional dopaminergic reward pathways. Fewer studies have examined the role of the serotonin (5-hydroxytryptamine; 5-HT) system in opioid addiction and relapse. Preliminary data in rodents indicate that stress interacts with opioid history to sensitize 5-HT dorsal raphe nucleus (DRN) neurons to GABAergic inhibition. More recent work identified a causal relationship between GABA signaling in the DRN and stress-induced opioid reinstatement. We hypothesize that this GABAergic sensitization results in serotonergic hypofunction and consequent dysphoric mood states which drive drug-seeking behaviors and therefore confer vulnerability to stress- induced opioid relapse. In the current application, we will employ two state-of-the-art genetic mutational strategies using the Cre-loxP system to engineer mice that are deficient in GABAA receptors selectively in the DRN or specifically in 5-HT neurons. First, we will confirm DRN- or 5-HT-specific deletion of the GABAA receptor in these mice using immunohistochemistry, electrophysiology and quantitative autoradiography. Next, we will test these mice in two complementary animal models of relapse in which a swim stress is used to reinstate previously extinguished morphine conditioned place-preference or self-administration. We predict that these mice will be protected from the GABAergic sensitization observed in the 5-HT DRN system following a stress-induced relapse model and will thus be less vulnerable to relapse in these two models. These studies will generate innovative animal models of opiate relapse resistance that will be a valuable tool to elucidate novel circuitry within the 5-HT DRN system that contribute to opiate relapse. This approach may identify novel targets for the treatment of opiate addiction and the prevention of relapse.