Selective serotonin reuptake inhibitors (SSRI) are common first-line treatments for major depression. However, a significant number of depressed patients do not respond adequately to these pharmacological treatments. In the present preclinical study, we demonstrate that organic cation transporter 2 (OCT2), an atypical monoamine transporter, contributes to the effects of SSRI by regulating the routing of the essential amino acid tryptophan to the brain. Contrarily to wild-type mice, OCT2-invalidated mice failed to respond to prolonged fluoxetine treatment in a chronic depression model induced by corticosterone exposure recapitulating core symptoms of depression, i.e., anhedonia, social withdrawal, anxiety, and memory impairment. After corticosterone and fluoxetine treatment, the levels of tryptophan and its metabolites serotonin and kynurenine were decreased in the brain of OCT2 mutant mice compared to wild-type mice and reciprocally tryptophan and kynurenine levels were increased in mutants plasma. OCT2 was detected by immunofluorescence in several structures at the blood-cerebrospinal fluid (CSF) or brain-CSF interface. Tryptophan supplementation during fluoxetine treatment increased brain concentrations of tryptophan in wild-type and OCT2 mutant mice, yet more efficiently in WT than in mutants, while discretely increasing 5-HT concentrations. Importantly, tryptophan supplementation improved the sensitivity to fluoxetine treatment of OCT2 mutant mice, impacting chiefly anhedonia and short-term memory. Western blot analysis showed that glycogen synthase kinase-3{beta} (GSK3{beta}) and mammalian/mechanistic target of rapamycin (mTOR) intracellular signaling was impaired in OCT2 mutant mice brain after corticosterone and fluoxetine treatment and, conversely, tryptophan supplementation recruited selectively the mTOR protein complex 2. This study provides the first evidence of the physiological relevance of OCT2-mediated tryptophan transport, and its biological consequences on serotonin homeostasis in the brain and SSRI efficacy.
