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.
