Physiological genomics of antidepressant targets: Keeping the periphery inmind

The plasma membrane transporters that clear extracellular serotonin (5-HT) and norepinephrine (NE), serotonin transporters (SERTs) and NE transporters (NETs), have received considerable attention over the past four decades be cause of their roles in amine neurotransmitter inactivation. In addition, t hey interact with many centrally active drugs, including multiple classes o f antidepressants such as the serotonin-selective reuptake inhibitors, typi fied by fluoxetine (Prozac), and the more recently developed norepinephrine -selective transporter antagonists, such as reboxetine. The therapeutic uti lity of these agents supports biogenic amine theories of affective disorder s and raises the question as to whether SERT and NET exhibit a functional g enetic variation that could influence risk for behavioral disorders. Althou gh evidence exists that a promoter polymorphism in SERT may influence behav ioral states, this contention is not without complexity and its mechanism o f action remains poorly understood. The identification of coding variants o f NETs and SERTs would offer important opportunities to connect genotype to phenotype. However, given the limited frequency of transporter coding vari ations evident to date in general population surveys or in psychiatric gene tic studies, the identification of informative functional variants of trans porters will likely require refined phenotypes. In this regard, NET and SER T play critical roles in cardiovascular and gastrointestinal physiology, re spectively. This perspective reviews recent human and mouse studies that su ggest how peripheral autonomic phenotypes, linked to genetic disruption of NET and SERT function, can aid in the phenotypic segregation needed for adv anced theories of biogenic amine dysfunction and pharmacogenetics.