SEROTONERGIC GENE FUNCTION AND BEHAVIOR IN TRANSGENIC MICE

家庭和双胞胎研究表明， 酒精中毒的发展。由于某些类型的酒精中毒是 与血清素周转减少有关，我们专注于 遗传决定因素，以确定因素 导致了酗酒倾向在中缝神经元中， 5-羟色胺的生物合成受色氨酸的活性控制， 羟化酶（TPH）酶，血清素中的限速酶 生物合成色氨酸的水平，血清素的前体， 由色氨酸2，3-双加氧酶（TDO）控制。血清素5 HT-1A 受体部分调节血清素的作用。我们假设 TPH、TDO和5-羟色胺5-HT-1A受体的遗传调节， 控制其基因表达的因素在血清素中起主要作用， 影响行为。小鼠TPH的cDNA和基因编码， 以前克隆的这些序列已经与来自 荧光素酶、HSV胸苷激酶和小鼠金属硫蛋白。这些是 被引入到小鼠胚胎中以制造转基因小鼠来研究 控制组织特异性和发育表达的基因序列， 以表征高和低TPH基因活性的影响，并 确定切除表达TPH的细胞对行为的影响。

Family and twin studies have implicated a genetic contribution to the development of alcoholism. Since certain types of alcoholism are associated with decreased serotonin turnover, we have focused on the genetic determinants of serotonergic behaviors to identify factors contributing to a predisposition to alcoholism. In the raphe neurons, serotonin biosynthesis is governed by the activity of the tryptophan hydroxylase (TPH) enzymes, the rate-limiting enzymes in serotonin biosynthesis. The levels of tryptophan, the precursor of serotonin, is controlled by tryptophan 2,3-dioxygenase (TDO). The serotonin 5HT-1A receptor modulates, in part, the action of serotonin. We hypothesize that the genetic regulation of TPH, TDO and the serotonin 5-HT-1A receptor and factors controlling their gene expression play a major role in serotonin- influenced behaviors. The cDNA and gene coding for murine TPH were previously cloned. These sequences have been combined with sequences from luciferase, HSV thymidine kinase and mouse metallothionein. These are being introduced into mouse embryos to create transgenic mice to study gene sequences controlling tissue-specific and developmental expression, to characterize effects of high and low TPH gene activity, and to determine the effects of ablation of TPH-expressing cells on behavior.