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: 6700844
• 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 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700844
• 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找到与可卡因戒断相关的情绪障碍的新疗法。 可卡因滥用的主要问题是戒酒一段时间后恢复可卡因的使用（复发）。 可卡因复发的促成因素是戒断引起的焦虑和抑郁症，刺激重新服用作为自我药物的形式。 从可卡因中提取会导致5-羟色胺2a（5-HT2A）受体的超敏性。 5-HT2A受体超敏反应与抑郁和焦虑有关。 因此，治疗5-HT2A受体超敏反应可能会减轻有助于可卡因复发的焦虑和抑郁。 但是，迄今为止，尚无研究调查导致可卡因诱导的5-HT2A受体超敏的机制。 拟议的研究将研究从可卡因退出诱导5-HT2A受体介导的激素分泌的超敏性的机制。 此外，将测试两种潜在的治疗方法，以扭转可卡因戒断期间突触后5-HT2A受体的超敏反应。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传导级联的特定成分的变化所致。 拟议的研究将研究下丘脑旁腔室中5-HT2A受体系统在从可卡因退出后及其对治疗的反应后的超敏性的信号传导机制。 AIM 1将确定可卡因注射天数的最小数量，该天数将产生5-HT2A受体信号传导的超敏反应。 药物依赖的特征之一是必须在出现戒断作用之前反复给药。 AIM 2将确定暴露于可卡因后5-HT2A受体的超敏性开始，并确定这些影响是否不可逆。 这项研究还将建立用于目标3-4的治疗参数。 可卡因戒断效应可能是由于5-HT释放而导致的5-HT2A受体的补偿性超敏反应。 因此，AIM 3将确定如何通过选择性单胺氧化酶A（MAO-A）抑制剂增加突触中5-HT的水平来逆转可卡因的戒断效应。 AIM 4将确定如何通过5-HT2A拮抗剂逆转可卡因对5-HT2A受体的戒断作用。 我们从选择性5-HT2A拮抗剂和MAO-A抑制剂治疗的研究中的结果可能会导致新型的治疗方法逆转5-HT2A受体的超敏性，从而治疗与可卡因戒断和复发相关的情绪障碍。