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

Abstract

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.