Tyrosine hydroxylase (tyrosine 3-monooxygenase, EC 1.14.16.2, TH) is the rate-limiting enzyme in the biosynthesis of catecholamine neurotransmitters, dopamine (DA), noradrenaline (NE), and adrenaline, in the neurons. The regulated activity of TH is thought to play a critical role in modulating the functional activity of catecholaminergic neuronal systems in the brain. It is well known that the catecholaminergic neuronal systems are associated with depression. Here we showed that TH, delivered by protein transduction domain (PTD), passed through the blood-brain barrier and entered the neurons. Systemic TH treatment improved the behavioral despair in the forced swim test (FST) and the tail suspension test (TST), the two models widely used to screen the potential anti-depressant efficacy. The results indicated a novel and potential therapeutic use of TH in the depression disorder. (c) 2006 Elsevier Inc. All rights reserved.