Depression and antidepressants: Insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters

Major depressive disorder (MDD) which is supposed to result from a complex interaction of genetic and epigenetic, environmental and developmental factors is one of the most common debilitating public health problems. The molecular mechanisms underlying this disease are still largely unclear. Identifying common pathways for diverse antidepressants (ADs) as well as new drug targets and thereby developing more effective treatments are primary goals of research in this field. Major targets of ADs are the serotonin transporter (SERT), the noradrenaline transporter (NAT) and also the dopamine transporter (DAT) located in the plasma membrane of corresponding neurons. These monoamine transporters (MATs) are important regulators of the extracellular neurotransmitter concentration. Among the clinically important ADs are tricyclic ADs (e.g. imipramine), selective serotonin re-uptake inhibitors (SSRIs, e.g. fluoxetine), selective noradrenaline (NA) re-uptake inhibitors (SNRIs, e.g. reboxetine) and NAT/DAT inhibitors like bupropion. This review is focussing on brain changes in monoamine neurotransmitter systems, downstream targets of monoaminergic neurotransmission as well as of behaviours of mice with a conventional knockout (KO) of either the SERT, DAT or NAT. MAT knockout induces changes in behaviour and brain neurochemistry. Although at least NATKO and SERTKO mice were expected to show a phenotype like AD-treated wild-type mice, this holds true only for the NATKO mice whereas SERTKO mice show an anxiety-like phenotype. Chronic social or restraint stress-induced depression-like behaviour and concomitant changes in brain neurotrophins are prevented by pharmacologically diverse ADs and by NATKO. Thus, NATKO mice are an interesting tool to investigate the mechanisms beyond monoamines responsible for depression as well as for AD actions. (C) 2010 Elsevier Inc. All rights reserved.