TREATMENT OF COCAINE-INDUCED 5-HT DYSFUNCTION

可卡因引起的 5-HT 功能障碍的治疗

• 批准号: 6846569
• 负责人: GEORGE BATTAGLIA
• 金额: $ 33.3万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846569
• 关键词: G protein; MAO inhibitors; anxiety; behavioral /social science research tag; biological signal transduction; cocaine; depression; drug abuse chemotherapy; drug abuse prevention; drug addiction; drug administration rate /duration; drug withdrawal; immunocytochemistry; in situ hybridization; laboratory rat; molecular pathology; mood disorders; neuroanatomy; neuroendocrine system; nonhuman therapy evaluation; receptor coupling; relapse /recurrence; serotonin inhibitor; serotonin receptor

The long term objective of this program is to find novel treatments for the mood disorders associated with cocaine withdrawal. A major problem with cocaine abuse is the return to cocaine use after a period of abstinence (relapse). contributing factor to cocaine relapse is withdrawal-induced anxiety and depression which stimulate re-administration as form of self-medication. Withdrawal from cocaine results in supersensitivity of serotonin-2A (5-HT2A ) receptors. 5-HT2A receptor supersensitivity is associated with depression and anxiety. Therefore, treating 5-HT2A receptor supersensitivity may alleviate the anxiety and depression that contribute to cocaine relapse. However, to date, no studies have investigated the mechanisms responsible for cocaine-induced 5-HT2A receptor supersensitivity. The proposed studies will investigate the mechanisms through which withdrawal from cocaine induces supersensitivity of 5-HT2A receptor-mediated secretion of hormones. In addition, two potential therapeutic approaches will be tested to reverse the supersensitivity of post-synaptic 5-HT2A receptors during cocaine withdrawal. Our hypothesis is that the cocaine-induced changes in sensitivity of 5-HT2A receptors are due to changes in specific components of the intracellular signaling cascade. The proposed studies will investigate signaling mechanisms underlying the supersensitivity of 5-HT2A receptor systems in the hypothalamic paraventricular nucleus after withdrawal from cocaine and their response to treatment. Aim 1 will determine the minimum number of cocaine injection days that will produce supersensitivity of 5-HT2A receptor signaling. One of the characteristics of drug dependence is that a drug must be administered repeatedly before withdrawal effects appear. Aim 2 will determine the onset of supersensitivity of 5-HT2A receptors after exposure to cocaine and to determine whether these effects are irreversible. This study also will establish the treatment parameters to be used in aims 3-4. The cocaine withdrawal effect may be a compensatory supersensitivity of 5-HT2A receptors due to reduced 5-HT release. Thus, Aim 3 will determine how the cocaine withdrawal effects on 5-HT2A receptors can be reversed by increasing the levels of 5-HT in the synapse with selective monoamine oxidase-A (MAO-A) inhibitors. Aim 4 will determine how the cocaine withdrawal effects on 5-HT2A receptors can be reversed by 5-HT2A antagonists. Our results from these studies on the treatment with selective 5-HT2A antagonists and MAO-A inhibitors may lead to novel therapeutic approaches to reverse the supersensitivity of 5-HT2A receptors and hence treat mood disorders associated with cocaine withdrawal and relapse.

该计划的长期目标是寻找新的治疗方法来治疗与可卡因戒断相关的情绪障碍。 可卡因滥用的一个主要问题是戒断一段时间后重新使用可卡因（复发）。 导致可卡因复吸的因素是戒断引起的焦虑和抑郁，这会刺激以自我药疗的形式重新服用。 戒断可卡因会导致 5-羟色胺-2A (5-HT2A) 受体过度敏感。 5-HT2A 受体超敏感性与抑郁和焦虑有关。 因此，治疗 5-HT2A 受体超敏反应可能会减轻导致可卡因复吸的焦虑和抑郁情绪。 然而，迄今为止，还没有研究调查可卡因诱导的 5-HT2A 受体超敏性的机制。 拟议的研究将调查可卡因戒断诱导 5-HT2A 受体介导的激素分泌超敏性的机制。 此外，还将测试两种潜在的治疗方法，以逆转可卡因戒断期间突触后 5-HT2A 受体的超敏感性。我们的假设是，可卡因诱导的 5-HT2A 受体敏感性变化是由于细胞内信号级联的特定成分的变化所致。 拟议的研究将调查可卡因戒断后下丘脑室旁核 5-HT2A 受体系统超敏性背后的信号传导机制及其对治疗的反应。 目标 1 将确定产生 5-HT2A 受体信号超敏感性的最小可卡因注射天数。 药物依赖的特征之一是必须反复服用某种药物才能出现戒断效应。 目标 2 将确定接触可卡因后 5-HT2A 受体超敏反应的发生，并确定这些影响是否不可逆转。 这项研究还将确定目标 3-4 中使用的治疗参数。 可卡因戒断效应可能是由于 5-HT 释放减少而导致 5-HT2A 受体的代偿性超敏感性。 因此，目标 3 将确定如何通过使用选择性单胺氧化酶 A (MAO-A) 抑制剂增加突触中 5-HT 的水平来逆转可卡因戒断对 5-HT2A 受体的影响。 目标 4 将确定 5-HT2A 拮抗剂如何逆转可卡因戒断对 5-HT2A 受体的影响。 我们对选择性 5-HT2A 拮抗剂和 MAO-A 抑制剂治疗的研究结果可能会带来新的治疗方法来逆转 5-HT2A 受体的超敏感性，从而治疗与可卡因戒断和复发相关的情绪障碍。

项目成果

Computerized versus in-person brief intervention for drug misuse: a randomized clinical trial.

• DOI: 10.1111/add.12502
• 发表时间: 2014-07
• 期刊: Addiction (Abingdon, England)
• 作者: Schwartz RP;Gryczynski J;Mitchell SG;Gonzales A;Moseley A;Peterson TR;Ondersma SJ;O'Grady KE
• 通讯作者: O'Grady KE