Sakura 6, a synthetic serotonin transporter (SERT)-binding peptide, enhances the interaction between SERT and neuronal nitric oxide synthase. This interaction decreases SERT activity and its presence on the cell surface, augments auto-inhibition, lowers synaptic 5-HT release, and diminishes activity in the dorsal raphe nucleus, ultimately inducing an acute depressive phenotype in a mouse depression model.