Serotonin Transporters: Implications for Antidepressant Drug Development

Abstract

A BSTRACTDue to the complexity of the disease, several hypotheses exist to explain the etiology of depression. The monoamine theory of depression suggests that disruptions in the sero tonergic and noradrenergic systems result in depressive symptoms. Therefore, the serotonin transporter (SERT) has become a pharmacological target for treating these symptoms. This review will discuss what is known about the molecular interactions of antidepressants with SERT. The effects of antidepressants on SERT regulation and expression in addition to the receptors that may be involved in mediating these effects will be addressed. Specifically, how changes to SERT expression following chronic antidepressant treatment may contribute to the therapeutic benefi ts of antidepressants will be discussed. Furthermore, the effects of SERT gene polymorphisms on antidepressant effi cacy will be examined. Finally, a brief overview of other hypotheses of depression will be addressed as well as factors that must be considered for future antidepressant development. K EYWORDS:SSRIs , antidepressant , serotonin transporter , depression , reuptake MONOAMINE THEORY OF DEPRESSIONFunctional defi ciencies in serotonin (5-hydroytryptamine, 5-HT) and norepinephrine (NE) have been implicated in the pathophysiology of depressive syndromes, and restoring the normal function of 5-HT-and NE-associated signaling pathway has been the target of antidepressants. Restoration of monoamine defi ciencies to normal levels as a therapeutic strategy is based on the monoamine hypothesis of depression. 1 The oldest antidepressants, the monoamine oxidase inhibitors (MAOIs), increase synaptic levels of 5-HT and NE by inhibiting the enzymatic degradation of these neurotransmitters. The tricyclic antidepressants (TCAs), as well as newer selective 5-HT reuptake inhibitors (SSRIs) and 5-HT/ NE reuptake inhibitors (SNRIs), all increase synaptic levels of 5-HT or NE by inhibiting reuptake via the 5-HT transporter (SERT) or NE transporter (NET), respectively. Emerging evidence indicates that the monoamine hypothesis of 5-HT and NE modulation fails to explain the whole mechanism of antidepressants. Other hypotheses, including the cytokine hypothesis of depression, the hypothalamic-pituitary-thyroid hypothesis of depression, as well as the role of brain-derived neurotrophic factor and cyclic AMP response element binding protein will be considered later in this review.

Overview of the pharmacogenomics of cigarette smoking

“…116,117 The serotonin transporter gene (5-HTT or SLC6A4) has been implicated in a number of psychiatric disorders such as depression and schizophrenia, both of which have high rates of co-morbidity with smoking. [118][119][120][121] A 44-bp insertion (L-allele) or deletion (S-allele) polymorphism (5-HTTLPR) has been found in the promoter with the S-allele reducing transcription. 122 The evidence for the impact of 5-HTTLPR on smoking has been mixed; the S-allele occurred at a lower frequency in current smokers compared to former or never smokers, 123,124 but others have not found any associations with current smoking, age of smoking initiation, cigarette consumption, Fagerstrom Tolerance Questionaire (FTQ) scores or previous quit history.…”

Two allelic isoforms of the serotonin transporter from Schistosoma mansoni display electrogenic transport and high selectivity for serotonin

“…The serotonin transporter (SERT) has been cloned from several mammalian species (Mortensen et al, 1999) and also from the nematode Caenorabditis elegans (Ranganathan et al, 2001). The SERT clears serotonin from the extracellular space using the sodium gradient as thermodynamic driving force (Torres et al, 2003) and is also the target for a major class of antidepressants (White et al, 2005). …”

Association of Changes in Norepinephrine and Serotonin Transporter Expression with the Long-Term Behavioral Effects of Antidepressant Drugs

“…For many antidepressants, including the tricyclic antidepressants, serotonin reuptake inhibitors (SRIs), norepinephrine reuptake inhibitors (NRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs), this results from inhibition of the norepinephrine or serotonin transporters (NET, SERT), which clear the transmitters from the synapse (Beyer et al , 2002; Katz et al , 2004; Morilak and Frazer, 2004; White et al , 2005). Some drugs enhance monoaminergic neurotransmission by other mechanisms such as inhibition of monoamine oxidase (Laux et al , 1995; López-Muñoz et al , 2007) or antagonism of presynaptic α-2 adrenergic receptors (Charney et al , 1986; Dickinson, 1990; Millan et al , 2000; Artigas et al , 2001).…”