Since alcoholism is associated with decreased serotonin turnover, we have focused on genetic determinants of serotonergic behaviors to identify factors contributing to a predisposition to alcoholism. In neurons, of the raphe nuclei, serotonin biosynthesis is governed by the activity of the tryptophan hydroxylase (TPH) enzyme, which is rate-limiting. The cDNA and gene coding for murine TPH were previously cloned. These sequences have been combined with sequences from HSV thymidine Kinase and mouse metallothionein genes. These are being introduced into mouse embryos to create transgenic mice to study gene sequences controlling tissue-specific and developmental expression and to characterize effects of high and low TPH gene activity and ablation of TPH-expressing cells on behavior.