Mood disorders cause much suffering and are the single greatest cause of lost 
productivity worldwide. Although multiple medications, along with behavioral 
therapies, have proven effective for some individuals, millions of people lack 
an effective therapeutic option. A common serotonin (5-HT) transporter 
(5-HTT/SERT, SLC6A4) polymorphism is believed to confer lower 5-HTT expression 
in vivo and elevates risk for multiple mood disorders including anxiety, 
alcoholism, and major depression. Importantly, this variant is also associated 
with reduced responsiveness to selective 5-HT reuptake inhibitor 
antidepressants. We hypothesized that a reduced antidepressant response in 
individuals with a constitutive reduction in 5-HTT expression could arise 
because of the compensatory expression of other genes that inactivate 5-HT in 
the brain. A functionally upregulated alternate transporter for 5-HT may prevent 
extracellular 5-HT from rising to levels sufficiently high enough to trigger the 
adaptive neurochemical events necessary for therapeutic benefit. Here we 
demonstrate that expression of the organic cation transporter type 3 (OCT3, 
SLC22A3), which also transports 5-HT, is upregulated in the brains of mice with 
constitutively reduced 5-HTT expression. Moreover, the OCT blocker decynium-22 
diminishes 5-HT clearance and exerts antidepressant-like effects in these mice 
but not in WT animals. OCT3 may be an important transporter mediating 
serotonergic signaling when 5-HTT expression or function is compromised.