SEROTONERGIC COMPONENT OF COCAINES ACTIONS

可卡因的众多作用被认为是由于其 刺激剂抑制摄取，从而增强 儿茶酚胺 最近，大量的体内生物化学， 电生理学和行为学的证据表明 这种兴奋剂也能对肾上腺素能神经元产生强有力的影响， 系统 这些研究表明，长期接触可卡因 血清素介导的受体的突触后超敏性 通过突触前缺乏血清素来发挥作用。 的机制 急性或慢性可卡因暴露改变了突触前 神经元5-羟色胺化学尚未完全了解， 研究系统地解决了这个问题。 5-羟色胺能受体包括至少四种类型（5-HT/1-4）。 在目前的建议中，最广泛使用的5-HT/2-受体模型， 小鼠的头部抽搐反应（HTR），将用于表征 急性和慢性可卡因给药的突触前效应 血清素神经系统 近日，申请人反映， 急性可卡因给药剂量依赖性地减弱DOI（a 直接5-HT/2-受体激动剂）诱导的HTR，而慢性给药 低剂量（0.03-1.25 mg/kg，i. p. Z）的兴奋剂增强DOI- 而高剂量的可卡因则没有影响。 在 目前的项目HTR将产生的血清素前体5- 羟色氨酸或5-HT吸收剂d-芬氟拉明。 这些试剂将 增加5-HT的突触浓度， 刺激突触后5-HT/2-受体，从而产生 HTR。 本议定书的具体目标是：1）确定 急性可卡因给药可能改变的突触前机制 由所引用的诱导剂产生的HTR。 比吸收利用率 5-HT、DA和NE的抑制剂将有助于描绘多巴胺能神经元的分布。 和可卡因对诱导行为的非兴奋性作用; 2） 确定慢性可卡因暴露的剂量和时间反应效应 对所引用的HTR诱导剂产生的HTR的影响。 这些研究将有助于 不仅揭示了可卡因对5- HT/2受体功能，但也将显示可卡因是否可以影响 突触前功能池和5-HT储存池。 这些研究 这一点很重要，因为急性和慢性可卡因接触 影响由直接激动剂DOI和所引用的 间接突触前机制 此外，长期接触可卡因可能 也不同地影响突触前HTR诱导剂。

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.