TREATMENT OF COCAINE-INDUCED 5-HT DYSFUNCTION

该计划的长期目标是为与可卡因戒断相关的情绪障碍找到新的治疗方法。可卡因滥用的一个主要问题是在戒除一段时间后重新使用可卡因(复发)。导致可卡因复发的因素是戒断引起的焦虑和抑郁，这些焦虑和抑郁刺激了作为自我用药形式的重新给药。戒断可卡因会导致5-羟色胺-2A(5-HT2A)受体超敏。5-HT2a受体超敏与抑郁和焦虑有关。因此，治疗5-HT2A受体超敏可能会减轻导致可卡因复发的焦虑和抑郁。然而，到目前为止，还没有研究探讨可卡因诱导的5-HT2A受体超敏的机制。这项拟议的研究将探讨戒断可卡因导致5-HT2A受体介导的激素分泌超敏的机制。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受体的超敏反应。我们的假设是，可卡因引起的5-HT2A受体敏感性的变化是由于细胞内信号级联的特定成分的变化。这项拟议的研究将探讨下丘脑室旁核5-HT2A受体系统在戒断可卡因后超敏的信号机制及其对治疗的反应。目的1将确定产生5-HT2A受体信号超敏的可卡因注射的最少天数。药物依赖的特征之一是，在出现戒断效应之前，必须反复给药。目的2将确定暴露于可卡因后5-HT2A受体的超敏反应的开始，并确定这些效应是否不可逆转。这项研究还将确定AIMS 3-4中使用的治疗参数。可卡因戒断效应可能是由于5-羟色胺释放减少而引起的5-HT2A受体的代偿性超敏反应。因此，目标3将确定如何通过增加突触中选择性单胺氧化酶-A(MAO-A)抑制剂的5-羟色胺水平来逆转可卡因戒断对5-HT2A受体的影响。目的4将确定5-HT2A受体上的可卡因戒断效应如何被5-HT2A拮抗剂逆转。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导致新的治疗方法，逆转5-HT2A受体的超敏反应，从而治疗与可卡因戒断和复发相关的情绪障碍。

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.