Activity and expression of tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine synthesis, are modified in response to antidepressant-treatment. We examined effects of the selective norepinephrine-transporter (NET) inhibitor antidepressant desipramine (DMI) on expression of TH in human neuroblastoma cells (SK-N-BE[2]M17) and in rat brain regions. TH mRNA levels were determined by Northern blot in vitro, and by in situ hybridization ex vivo; TH protein levels were measured by western blot. Brief exposure of neuroblastoma cells to 0 vs. 5, 50, or 500 nM of DMI had little effect on TH mRNA levels, but exposure to 50 and 500 nM DMI for 14 days increased the mRNA by up to 72%, with a continuous rise from 3 to 14 days of exposure to 500 nM DMI. In contrast, 500 nM DMI led to an initial slight increase, followed by a continuous and sustained decrease in TH protein level by up to 53%, from day 3 to day 14. Daily treatment of rats with DMI (10 mg/kg, i.p.) for 3 or 14 days significantly increased postmortem cerebral TH mRNA in the locus coeruleus (LC) area by 47-68%. Again, TH protein concentrations in LC decreased at 3 and 14 days, by 25-40%, with transient significant reduction in amygdala tissue after 3 days of treatment that were not sustained. These findings indicate that DMI exerts complex, typically opposite and perhaps compensatory, gradually evolving effects on the expression of TH protein (decreases) and its message (increases), possibly in response to increased synaptic availability of NE.