Manta, S. | Search bioRxiv

bioRxiv2026

Fluoxetine-induced neurogenesis and chronic antidepressant effects requires the dopamine D2 receptor.

Major depressive disorder (MDD) is a common psychiatric illness with a high proportion of patients being nonresponsive to therapy. Selective serotonin reuptake inhibitors (SSRI) are widely prescribed for treating depression. Chronic SSRI administration is needed for therapeutic effects, a process implicating in part, increased neurogenesis in the hippocampus. Recent genome wide association studies (GWAS) identified the DrD2 locus, which encodes the dopamine D2 receptor (D2R) as a major risk factor in MDD. Here we demonstrate that behavioural effects associated with chronic administration of the SSRI drug fluoxetine and its accompanying neurogenic effects require D2R. Administration of fluoxetine to congenital D2R-knockout mice, or co-administration of the antidepressant with the antipsychotic D2R antagonist drug haloperidol prevented the neurogenic effects of fluoxetine. Furthermore, while acute behavioural responses to fluoxetine did not require D2R, this receptor was essential for the behavioural effects of chronic fluoxetine. The neurogenic impact of chronic fluoxetine was further associated with beta-arrestin 2-mediated signalling and the hippocampal regulation of the pro-neurogenic factor BDNF. These results support a role of D2R in regulating the therapeutically relevant chronic effects of fluoxetine on mood, BDNF signalling, and associated hippocampal neurogenesis. Furthermore, our findings suggest an unappreciated interaction between genetic risk for MDD and treatment responsiveness as well as a negative interaction between SSRIs and antipsychotic drugs in the regulation of hippocampal neurogenesis.

neuroscience↗

bioRxiv2023

Organic cation transporter 2 contributes to SSRI antidepressant efficacy by controlling tryptophan availability in the brain

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.

neuroscience↗