Antidepressant-induced internalization of the serotonin transporter in serotonergic neurons

A deficiency of serotonergic signaling is thought to be involved in the etiology of depression. Thus, drugs blocking the reuptake of serotonin back into the neurons are widely used in treatment of this disease; however, their delayed effect in remission of patients suggests that the clinical response does not rely on simple serotonin uptake inhibition but may include further regulatory mechanisms. We have analyzed cellular serotonin transporter (SERT) expression on exposure to the selective serotonin reuptake inhibitor citalopram in serotonergic neurons expressing the native SERT allele in its natural surroundings. Biotinylation of SERT-expressing HEK293 cells, as well as confocal microscopy analysis in these cells and in serotonergic neurons, revealed that exposure to citalopram time dependently reduces the amount of cell surface-expressed SERT. Furthermore, in serotonergic neurons, longer exposure to citalopram not only caused an internalization of SERT proteins from the cell surface but also induced a redistribution of SERT from neurite extensions into the soma. This process was reversible on drug removal. Microarray analysis performed on citalopram-treated serotonergic neurons revealed that antidepressant treatment does not alter SERT mRNA expression, suggesting that SERT trafficking from and to the cell membrane is regulated on the posttranscriptional level.