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Opioids & plasticity in regulation of serotonin release

阿片类药物

基本信息

批准号：
6940575
负责人：
RUI TAO
金额：
$ 17.56万
依托单位：
FLORIDA ATLANTIC UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2006-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6940575
关键词：
aerobic exercise chordate locomotion dorsal raphe nucleus endogenous opioid gamma aminobutyrate glutamates hippocampus laboratory rat neural plasticity neural transmission neuropharmacology neurotransmitter transport psychopharmacology serotonin

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this project is to understand the physiological and pathological mechanisms of opioid-mediated plasticity in the neural circuitry controlling serotonin (5-HT) release in the mammalian forebrain, and thereby provide a sound basis for understanding and treatment of psychiatric disorders such as depression and drug addiction. The experimental approach combines behavioral measures with microdialysis in the CNS of freely behaving rats. We propose that mu, delta, kappa and ORL-1 opioids have different roles in regulation of 5-HT release. By reverse microdialysis infusion of selective opioid receptor agonists into the dorsal raphe nucleus (DRN) we will test the specific hypothesis that mu- and delta-opioids produce increases, and kappa- and ORL-1 decreases in 5-HT release. We further hypothesize that opioids have regionally selective effects on 5-HT. Preliminary data indicate that mu- and delta- opioids act in the DRN to increase 5-HT release in specific forebrain projection sites. In contrast, kappa-opioids may inhibit 5-HT release by acting on terminals in widespread areas of the brain including the DRN, median raphe nucleus, nucleus accumbens and dorsal hippocampus. The hypothesis that the increase in 5-HT elicited by mu-opioids is mediated indirectly by neural circuitry will also be examined. Specifically, mu-opioids may inhibit both GABAergic and glutamatergic inputs to 5-HT neurons in the DRN. This hypothesis will be investigated by using selective GABA and glutamate receptor antagonists to characterize the tonic activity of inhibitory and excitatory influences on 5-HT neurons. Preliminary data indicate a strong tonic influence of GABA compared with a relatively weak effect of glutamate in the DRN. We propose experiments to further examine the hypothesis that the effect of mu-opioids on 5-HT can be attributed to direct inhibition of both GABA and glutamate neurons. Because, GABA tone is predominant, the net effect of inhibiting both inputs is an increase in 5-HT release. In contrast, kappa- and ORL-1-opioids may directly inhibit 5-HT neurons. Prolonged opioid treatment may produce plasticity in the strength of synaptic connections in the raphe and thus affect the regulation of 5-HT release. To examine this hypothesis, opioid dependence will be induced by either direct infusion of opioids into the DRN for 4 days or by subcutaneous implantation of morphine pellets. Based on our previous observations, we will test the hypothesis that mu-opioids cause adaptations in 5-HT release by enhancement of GABA inputs. Similarly, the possibility of enhanced glutamate synaptic transmission will be tested. By determining changes in 5-HT during withdrawal, we will test the specific hypothesis that the enhancement in GABA exceeds the change in glutamate. This may result in a more pronounced net inhibitory effect of afferent inputs, thus decreased 5-HT release after tolerance to opioids develops. Further experiments will test the hypothesis that the excitability of 5-HT neurons is increased after prolonged treatment with ORL-1 opioids. Finally, we will test the hypothesis that 5-HT release is enhanced after regular exercise and this may ameliorate the adverse consequences of prolonged opioid treatment. Recent data suggest that the increase in 5-HT release associated with treadmill locomotion is enhanced after regular exercise. To examine the role of exercise in alleviating behavioral depression, opioid-dependent rats will be exercised regularly on a treadmill. We hypothesize that regular exercise results in an increase in the strength of glutamate relative to GABA connections with 5-HT neurons in the DRN, and that this may normalize the enhancement in net inhibitory associated with prolonged exposure to opioids.

描述（由申请人提供）：本项目的总体目标是了解阿片介导的生理和病理机制，控制5-羟色胺（5-HT）释放的神经回路的可塑性哺乳动物前脑，从而为理解和治疗精神疾病，如抑郁症和药物成瘾。的实验方法将行为测量与微透析相结合，自由行为大鼠的CNS。我们认为mu，delta，kappa和ORL-1阿片类药物在调节5-HT的释放。通过反向微透析输注选择性阿片受体激动剂进入中缝背核（DRN），我们将测试 μ-和δ-阿片类药物产生增加的具体假设，以及κ- ORL-1降低5-HT释放。我们进一步假设阿片类药物对5-HT的区域选择性作用。初步数据显示， δ-阿片类药物作用于DRN，增加特定前脑中5-HT的释放投影点。相比之下，κ-阿片类药物可能通过作用于5-HT而抑制5-HT的释放。在大脑广泛区域的终端，包括DRN，中缝核、背侧海马核和背侧海马。 μ-阿片类药物引起的5-HT增加是介导的还将检查间接通过神经回路进行的研究。特别是μ阿片类药物可能抑制对DRN中5-HT神经元的GABA能和多巴胺能输入。这一假设将通过使用选择性GABA和谷氨酸来研究受体拮抗剂，以表征抑制和对5-HT神经元的兴奋性影响。初步数据显示， GABA的影响与谷氨酸相对较弱的影响相比， DRN。我们提出实验来进一步检验这一假设， μ-阿片类药物对5-HT的作用可归因于对GABA和谷氨酸神经元因为GABA张力占主导地位，抑制这两种输入是5-HT释放的增加。相比之下，Kappa-和 ORL-1-阿片类物质可直接抑制5-HT神经元。长期阿片类药物治疗可使突触强度产生可塑性，连接在中缝，从而影响5-HT释放的调节。到检验这一假设，阿片类药物依赖将由直接或间接诱导。将阿片类药物输注到DRN中4天或通过皮下植入吗啡丸根据我们之前的观察，我们将测试 μ-阿片类药物通过增强5-HT释放引起适应假说 GABA输入。同样，增强谷氨酸突触的可能性传输将被测试。通过测定戒断过程中5-HT的变化，我们将测试特定的假设，即GABA的增强超过谷氨酸的变化这可能会导致更明显的净抑制作用因此，阿片耐受后5-HT释放减少发展起来的进一步的实验将检验这一假设，即 ORL-1阿片类药物延长治疗后5-HT神经元增加。最后，我们将测试的假设，即5-羟色胺释放增强后，定期运动，这可能会改善长期阿片类药物治疗最近的数据表明，5-HT释放的增加与跑步机运动相关的运动能力在定期锻炼后增强。到研究锻炼在缓解行为抑郁中的作用，阿片样物质依赖的大鼠将定期在跑步机上运动。我们假设经常锻炼会增加肌肉的力量，谷氨酸相对于GABA与DRN中5-HT神经元的连接，这可能使与延长的暴露于阿片类药物