INVIVO CHARACTERIZATION OF LOCALLY APPLIED DOPAMINE UPTAKE INHIBITORS BY STRIATAL MICRODIALYSIS
INVIVO CHARACTERIZATION OF LOCALLY APPLIED DOPAMINE UPTAKE INHIBITORS BY STRIATAL MICRODIALYSIS
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DOI：
10.1002/syn.890060113
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发表时间：
1990-01-01
期刊：
影响因子：
2.3
通讯作者：
FIBIGER, HC
中科院分区：
文献类型：
--
作者：
NOMIKOS, GG;DAMSMA, G;FIBIGER, HC
在体内脑微透析被用来表征多巴胺摄取抑制剂对多巴胺（DA）及其代谢产物二羟苯乙酸（DOPAC）和高香草酸（HVA）在清醒，自由活动的大鼠纹状体细胞外浓度的影响。d-安非他明、GBR 12909、可卡因、诺米芬辛、哌醋甲酯、安非他酮和苯扎托品通过灌注以递增浓度（1- 1，000 μ M）直接给药至纹状体。所有药物均以剂量依赖性方式增加细胞外DA;然而，仅d-苯丙胺产生DOPAC和HVA浓度的剂量依赖性降低。剂量反应函数的形状在药物之间有很大差异。在100和1000 μ M时，d-安非他明对透析液DA浓度具有双相作用（先增加后减少）。当以1，000 μ M浓度施用时，GBR 12909、哌甲酯和苯并托品也具有双相效应。相反，可卡因，诺米芬新，安非他酮产生相对单相增加细胞外DA。河豚毒素（TTX），阻止动作电位通过阻断电压依赖性Na+通道，并没有阻止d-苯丙胺诱导的细胞外DA的增加，但完全阻断可卡因，诺米芬新，安非他酮，哌甲酯的影响。虽然低剂量（10 μ M）的GBR 12909和苯并托品对TTX高度敏感，但该毒素对较高剂量的化合物仅部分有效。通过10或100 μ M产生的细胞外DA的增加确定的药物效力的等级顺序（在体外对测试化合物的透析效率进行校正后）为GBR 12909 >苯扎托品>安非他明=诺米芬辛=哌甲酯>可卡因>安非他酮。在直接，局部应用DA摄取抑制剂后，细胞外DA的变化的体内表征可用于提供有关这些化合物的作用机制和效力的有用信息。
In vivo brain microdialysis was used to characterize the effects of some dopamine uptake inhibitors on the extracellular concentration of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striata of awake, freely moving rats. d-Amphetamine, GBR 12909, cocaine, nomifensine, methylphenidate, bupropion, and benztropine were administered directly to the striatum via the perfusion in increasing concentrations (1-1,000 .mu.M). All drugs increased extracellular DA in a dose-dependent manner; however, only d-amphetamine produced dose-dependent decreases in DOPAC and HVA concentrations. The shapes of the dose-response functions differed considerably between the drugs. At 100 and 1000 .mu.M d-amphetamine had biphasic effects (an increase followed by a decrease) on dialysate DA concentrations. GBR 12909, methylphenidate, and benzotropine also had biphasic effects when applied at the 1,000 .mu.M concentration. In contrast, cocaine, nomifensine, and bupropion produced relatively monophasic increases in extracellular DA. Tetrodotoxin (TTX), which prevents action potentials by blocking voltage-dependent Na+ channels, did not prevent d-amphetamine induced increases in extracellular DA, but blocked completely the effects of cocaine, nomifensine, bupropion, and methylphenidate. While low doses (10 .mu.M) of GBR 12909 and benzotropine were highly sensitive to TTX, the toxin was only partially effective against higher doses of the compounds. The rank order of potency of the drugs as determined by the increases in extracellular DA produced by 10 or 100 .mu.M (following correction for dialysis efficiency of the test compounds in vitro) was GBR 12909 > benztropine > amphetamine = nomifensine = methylphenidate > cocaine > bupropion. The in vivo characterization of changes in extracellular DA following direct, local application of DA uptake inhibitors can be used to provide useful information about the mechanism of action and potency of these compounds.