We have produced lines of transgenic mice carrying multiple copies of the tryptophan hydroxylase (TPH) gene by pronuclear injection of TPH gene. TPH is the initial and rate-limiting enzyme in the biosynthesis of the neurotransmitter serotonin (5-HT). The synthesis of 5-HT can proceed only through this enzyme-catalyzed step. Serotonin is one of the known monoamine neurotransmitters, mitogens and hormones that mediate a wide variety of behavioral and physiological processes in the mammalian central nervous system. As an important neurotransmitter, 5-HT mediates pain, sleep, thermoregulation, food in-take, locomotion, and learning. From a clinical aspect, altered 5-HT function has been implicated in depression, obsessive-compulsive disorder, autism, and impulsive self-destructive behaviors such as aggression, suicide, schizophrenia, anxiety, insomnia, and drug abuse. In order to understand molecular mechanisms underlying the regulation of TPH gene expression, transgenic animals were produced by pronucleus injection of TPH cDNA under the transcriptional control of TPH 5'-upstream flanking genomic DNA fragment, so that in these transgenic mice, the TPH gene could be overexpressed in serotonergic cell types. Out of the microinjected 5,714 embryos transferred into the female oviduct, 110 offsprings were produced. Five transgenic founder lines were established as permanent lines. From cellular phenotypic characterization using 5-HT immunohisto-chemistry, the transgenic lines were confirmed to produce increased immunoreactivity compared to their non-transgenic littermates. To measure behavioral characteristics of transgenic lines harboring more than sixty copies of the TPH gene, the folowing tests were performed: motility test, elevated plus maze test, Y-maze test, passive avoidance, and climbing behavior test. Among the behavioral tests, the transgenic animals exhibited significantly more locomotive activity than the control littermate siblings. Details of the behavioral profiles obtained by measuring behaviors of these transgenic mice will be presented.

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