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断一段时间后重新使用可卡因（复发）。 可卡因复吸的促成因素是戒断引起的焦虑和抑郁，这刺激了作为自我药疗形式的再次给药。 可卡因戒断导致5-羟色胺-2A（5-HT 2A）受体超敏。 5-HT 2A受体超敏性与抑郁和焦虑有关。 因此，治疗5-HT 2A受体超敏性可能会减轻导致可卡因复吸的焦虑和抑郁。 然而，迄今为止，没有研究调查可卡因诱导的5-HT 2A受体超敏性的机制。 拟议的研究将调查可卡因戒断诱导5-HT 2A受体介导的激素分泌超敏性的机制。 此外，将测试两种潜在的治疗方法来逆转可卡因戒断期间突触后5-HT 2A受体的超敏性。我们的假设是可卡因诱导的5-HT 2A受体敏感性的变化是由于细胞内信号级联的特定组分的变化。 拟议的研究将调查信号机制的5-HT 2A受体系统在下丘脑室旁核的超敏性后，从可卡因和他们的反应，以治疗戒断。 目标1将确定将产生5-HT 2A受体信号传导超敏性的可卡因注射天数的最小值。 药物依赖的特征之一是，药物必须反复给药，才能出现戒断效应。 目的2将确定暴露于可卡因后5-HT 2A受体超敏反应的发生，并确定这些影响是否是不可逆的。 本研究还将确定用于目标3-4的治疗参数。 可卡因戒断效应可能是由于5-HT释放减少而引起的5-HT_（2A）受体的代偿性超敏反应。 因此，目标3将确定可卡因戒断对5-HT 2A受体的影响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。 目的4研究5-HT_（2A）受体拮抗剂如何逆转可卡因戒断对5-HT_（2A）受体的影响。 我们的结果从这些研究中选择性5-HT 2A拮抗剂和MAO-A抑制剂的治疗可能会导致新的治疗方法，以扭转5-HT 2A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。

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.