K-opioid receptor agonists produce conditional aversive and pro-depressant-like effects. SERT is one of the major determinants of synaptic 5-HT and serotonergic neurotransmission. K-opioid receptor activation decreases 5-HT uptake through Akt and CaMKII pathways. K-opioid receptor activation decreases surface SERT, increases phosphorylation and endocytosis. K-opioid receptor activation decreases serotonin clearance in the striatum.