Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine ("ecstasy") in serotonin transporter-deficient mice
Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine ("ecstasy") in serotonin transporter-deficient mice
复制标题
DOI：
10.1124/mol.53.4.649
复制
发表时间：
1998-04-01
影响因子：
3.6
通讯作者：
Lesch, KP
中科院分区：
文献类型：
--
作者：
Bengel, D;Murphy, DL;Lesch, KP
钠依赖性、高亲和力5-羟色胺[5-羟色胺（5-HT）]转运蛋白（5-HTT）提供了5-HT释放到突触间隙后失活的主要机制。为了进一步评价5-HTT的功能，通过同源重组破坏鼠基因。尽管有证据表明，在胚胎发育过程中过量的细胞外5-HT，包括抑制5-HTT的药物产生的细胞外5-HT，可能导致严重的颅面和心脏畸形，但在5-HTT-/-小鼠中没有观察到明显的发育表型。高亲和力[H-3]5-HT摄取在5-HTT-/-小鼠中完全不存在，证实了5-HTT基因的生理学有效敲除。5-用[I-125]3 β-（4 '-碘苯基）托品烷-2 β-羧酸甲酯标记的HTT结合位点以基因剂量依赖性方式减少，在5-HTT-/-突变体中没有明显的结合。在成年5-HTT-/-小鼠中，在几个脑区测量到5-HT浓度显著降低（60-80%）。虽然（+）-安非他明诱导的多动症在基因型之间没有差异，但（+）-3，4-亚甲二氧基甲基安非他明（一种通过转运蛋白依赖性机制释放5-HT的取代安非他明）的运动增强作用在5-HTT-/-突变体中完全不存在。总之，这些数据表明，功能性5-HTT的存在是必不可少的大脑5-HT稳态和3，4-亚甲二氧基甲基苯丙胺诱导的多动症。
The sodium-dependent, high affinity serotonin [5-hydroxytryptamine (5-HT)] transporter (5-HTT) provides the primary mechanism for inactivation of 5-HT after its release into the synaptic cleft. To further evaluate the function of the 5-HTT, the murine gene was disrupted by homologous recombination. Despite evidence that excess extracellular 5-HT during embryonic development, including that produced by drugs that inhibit the 5-HTT, may lead to severe craniofacial and cardiac malformations, no obvious developmental phenotype was observed in the 5-HTT-/- mice. High affinity [H-3]5-HT uptake was completely absent in 5-HTT-/- mice, confirming a physiologically effective knockout of the 5-HTT gene. 5-HTT binding sites labeled with [I-125]3 beta-(4'-iodophenyl)tropan-2 beta-carboxylic acid methyl ester were reduced in a gene dose-dependent manner, with no demonstrable binding in 5-HTT-/- mutants. In adult 5-HTT-/- mice, marked reductions (60-80%) in 5-HT concentrations were measured in several brain regions. While (+)-amphetamine-induced hyperactivity did not differ across genotypes, the locomotor enhancing effects of (+)-3,4-methylenedioxymethamphetamine, a substituted amphetamine that releases 5-HT via a transporter-dependent mechanism, was completely absent in 5-HTT-/- mutants. Together, these data suggest that the presence of a functional 5-HTT is essential for brain 5-HT homeostasis and for 3,4-methylenedioxymethamphetamine-induced hyperactivity.