SEROTONERGIC COMPONENT OF COCAINES ACTIONS

可卡因的众多行为被认为是由于 抑制摄取的刺激剂，从而增强 儿茶酚胺。最近，过多的体内生化， 电生理和行为证据已经出现，这些证据表明 刺激剂也会对5-羟色胺能产生强烈的影响 系统。这些研究表明，长期接触可卡因会导致 5-羟色胺介导受体的突触后超敏反应 通过突触前5-羟色胺缺乏发挥作用。这些机制由 急性或慢性可卡因暴露改变突触前 神经元5-羟色胺化学尚未完全了解，体内也没有 研究已经系统地解决了这个问题。 5-羟色胺能受体至少由四种类型组成(5-羟色胺/1-4)。 在本提案中，使用最广泛的5-羟色胺/2-受体模型，即 将利用小鼠的头部抽动反应(HTR)来表征 急性和慢性给予可卡因对大鼠突触前神经元的影响 5-羟色胺神经系统。最近，申请人报告说 急性给予可卡因呈剂量依赖性地减弱DOI(a 直接5-羟色胺/2-受体激动剂)诱导的HTR，同时慢性给药 低剂量(0.03-1.25 mg/kg，i.p.Z)的刺激剂可增强DOI- 诱导行为，而大剂量的可卡因不起作用。在 目前的项目HTR将由5-羟色胺前体5- 羟色氨酸或5-羟色胺释放剂d-芬氟拉明。这些特工将 增加突触中5-羟色胺的浓度将导致 刺激突触后5-羟色胺/2-受体，从而产生 HTR。本议定书的具体目标是：1)确定 急性给予可卡因可能改变的突触前机制 被引用的诱导剂产生的HTR。特定摄取的利用 5-羟色胺、多巴胺和去甲肾上腺素的抑制剂有助于描绘5-羟色胺能 和可卡因对诱导行为的非5-羟色胺能作用；2) 确定慢性可卡因暴露的剂量效应和时间效应 关于所引用的高温气冷堆诱导剂产生的高温气冷堆。这些研究将会有所帮助 不仅是为了揭示可卡因对5-5人的急性和慢性影响- HT/2受体的功能，但也将表明可卡因是否会影响 5-羟色胺的突触前功能池和储存池。这些研究是 重要的是因为急性和慢性可卡因暴露可以不同 影响直接激动剂DOI和被引用化合物产生的HTR 间接突触前机制。此外，长期接触可卡因可能会 也不同地影响突触前HTR诱导物。

The numerous actions of cocaine are thought to be due to the ability of the stimulant to inhibit the uptake and thus enhance the effects of catecholamines. Recently, a plethora of in vivo biochemical, electrophysiological and behavioral evidence has emerged which conclude that the stimulant also produces potent effects on the serotonergic system. These studies suggest that chronic cocaine exposure causes postsynaptic supersensitivity in serotonergically-mediated receptor functions via a presynaptic deficit in serotonin. The mechanisms by which either acute or chronic cocaine exposure alters presynaptic neuronal serotonin chemistry is not yet fully understood and no in vivo study has systematically addressed the issue. Serotonergic receptors are comprised of at least four types (5-HT/1-4). In the present proposal, the most widely used 5-HT/2-receptor model, the head-twitch response (HTR) in mice, will be utilized to characterize the presynaptic effects of both acute and chronic cocaine administration on the serotonin neuronal system. Recently, the applicant reported that acute cocaine administration dose-dependently attenuates the DOI (a direct 5-HT/2-receptor agonist)-induced HTR, while chronic administration of low doses (0.03-1.25 mg/kg, i.p.Z) of the stimulant enhances the DOI- induced behavior whereas high doses of cocaine has no effect. In the present project the HTR will be produced by the serotonin precursor 5- hydroxytryptophan or the 5-HT releaser d-fenfluramine. These agents will increase the synaptic concentration of 5-HT which will lead to the stimulation of postsynaptic 5-HT/2-receptors and therefore production of HTR. The specific aims of the present protocol are: 1) to determine the presynaptic mechanisms by which acute cocaine administration may modify the HTR produced by the cited inducers. Utilization of specific uptake inhibitors for 5-HT, DA and NE will help to delineate the serotonergic and nonserotonergic effects of cocaine on the induced behavior; 2) to determine the dose- and time-response effects of chronic cocaine exposure on the HTR produced by the cited HTR inducers. These studies will help not only to reveal the acute and chronic effects of cocaine on the 5- HT/2-receptor function but will also show whether cocaine can effect the presynaptic functional and storage pools of 5-HT. These studies are important because acute and chronic cocaine exposure can differentially affect the HTR produced by the direct agonist DOI and by the cited indirect presynaptic mechanisms. Moreover, chronic cocaine exposure may also differentially affect the presynaptic HTR inducers.