PERSISTENT COCAINE INDUCED CHANGES IN DOPAMINE CLEARANCE

反复间歇服用可卡因会导致行为 敏化。该项目的总体目标是确定 神经化学变化是造成这种持续现象的原因。这个 本申请中提出的实验将检验以下假设 多巴胺(DA)和5-羟色胺(5-HT)转运体的持续性变化 在特定的大脑区域的功能，以及持续的变化 可卡因在大脑中的处置，有助于可卡因的表达- 诱导的行为敏感化。最初的一系列实验将 研究大脑中增加的可卡因浓度所起的作用 行为敏感化。大脑中的药物水平更高 反复后，与急性腹膜腔内(Ip)相比。 可卡因的使用。预计情况不会是这样 静脉注射(静脉注射)行政管理。大脑可卡因水平将被测量 在急性重复静脉注射后。可卡因。此外，还将对其进行调查 是否重复静脉注射。服用可卡因会产生类似于 重复的I.P.在行为、DA审批和DA方面的管理 转运蛋白结合。在过去的资助期内，在体内 电化学(EC)记录被用来表征 外源性(局部应用)DA在背侧纹状体和 乌拉坦麻醉大鼠伏隔核(NAC)。这一衡量标准 清除反应了神经元的DA转运体功能。在第二组 实验，这些研究将扩展到检查清除 内源性多巴胺是对电刺激的反应而释放的。 麻醉大鼠。目的是比较内源性和外源性DA 通过率。第三组实验将检测可卡因诱导的 刺激诱发的背侧纹状体内源性多巴胺清除的变化 和未麻醉的自由行为大鼠的NAC。体内并发EC和 行为测量将检验这样一种假设，即 DA转运体，特别是在南美洲，与可卡因直接相关- 诱导的行为敏感化。反复、间歇性的影响 注射，这应该导致行为敏感化，并持续 输液，这应该会导致行为耐受，将进行比较。 最后一组实验将考察5-羟色胺在脑内的可能作用。 可卡因致敏。NAC细胞外5-羟色胺水平升高 内侧前额叶皮质(MPFC)5-羟色胺转运体结合部位 在可卡因致敏的大鼠身上也有报道。行为实验将 确定5，7-羟色胺选择性损毁5-羟色胺神经元 二羟色胺改变致敏反应的表达。外源性5-羟色胺 将使用NAC和NAC中的活体EC记录来表征清除率 麻醉大鼠的MPEC。随后，将确定是否5- 这两个脑区的羟色胺清除是不同的和持续的。 在反复服用可卡因后发生了改变。澄清： 动物行为敏感化的潜在机制(S)可能会增强我们的 预测和理解可卡因的长期后果的能力 滥用，包括药物引起的精神错乱。

Repeated intermittent administration of cocaine results in behavioral sensitization. The overall goal of this project is to identify neurochemical alterations responsible for this persistent phenomenon. The experiments proposed in this application will test the hypotheses that persistent changes in dopamine (DA) and serotonin (5-HT) transporter function in specific brain regions, as well as persistent changes in cocaine disposition in the brain, contribute to the expression of cocaine- induced behavioral sensitization. The initial set of experiments will examine the role played by increased brain concentrations of cocaine in behavioral sensitization. Higher drug levels are achieved in the brain following repeated, as compared to acute, intraperitoneal (i.p.) administration of cocaine. This is not expected to be the case with intravenous (i.v.) administration. Brain cocaine levels will be measured following acute and repeated i.v. cocaine. Also, it will be investigated whether repeated i.v. cocaine administration produces changes similar to repeated i.p. administration in terms of behavior, DA clearance and DA transporter binding. During the past funding period, in vivo electrochemical (EC) recording has been used to characterize the disappearance of exogenous (locally-applied) DA in dorsal striatum and nucleus accumbens (NAc) of urethane-anesthetized rats. This measure of clearance reflects neuronal DA transporter function. In the second set of experiments, these studies will be extended to examine the clearance of endogenous DA, released in response to electrical stimulation, in the anesthetized rat. The aim will be to compare endogenous and exogenous DA clearance rates. The third set of experiments will examine cocaine-induced changes in clearance of stimulation-evoked endogenous DA in dorsal striatum and NAc of unanesthetized, freely behaving rats. Concurrent in vivo EC and behavioral measurements will test the hypothesis that hypersensitivity of the DA transporter, particularly in NAc, is directly related to cocaine- induced behavioral sensitization. The effects of repeated, intermittent injections, which should result in behavioral sensitization, and continuous infusion, which should result in behavioral tolerance, will be compared. The final set of experiments will examine the possible role of 5-HT in cocaine sensitization. Increases in both extracellular 5-HT levels in NAc and 5-HT transporter binding sites in medial prefrontal cortex (MPFC) have been reported in cocaine-sensitized rats. Behavioral experiments will determine whether selective lesioning of 5-HT neurons with 5,7- dihydroxytryptamine alters expression of sensitization. Exogenous 5-HT clearance rate will be characterized using in vivo EC recording in NAc and MPEC of anesthetized rats. Subsequently, it will be determined whether 5- HT clearance in these two brain regions is differentially and persistently altered following repeated cocaine administration. Elucidation of the mechanism(s) underlying behavioral sensitization in animals may enhance our ability to predict and understand the long-term consequences of cocaine abuse, including drug-induced psychosis, in humans.