Experimental Models in Serotonin Transporter Research: Primate models in serotonin transporter research

ABSTRACT Numerous studies provide persuasive evidence that a polymorphism in the serotonin promoter, 5-HTTLPR, interacts with environmental risk factors to produce heightened rates of depression, anxiety, antisocial and borderline personality disorders, and substance abuse in adults and adolescents. Investigations with the rhesus monkey have demonstrated similar gene–environment (G×E) interactions on both behavioral and biological outcomes. In this chapter, we review the history of primate models in serotonin transporter (5-HTT) research. Work with non-human primates has noted associations between behavioral differences and variation in serotonin metabolism (5-hydroxy-indole acetic acid, 5-HIAA). Investigations in several non-human primate species have also indicated that manipulation of early experience results in changes in behavior along with alterations in serotonergic functioning. These lines of research have contributed to the discovery of short ( s ) and long ( l ) forms within the serotonin promoter (rh5-HTTLPR) in the rhesus monkey. Researchers have since documented associations between the l / s or s / s genotypes and reduced cognitive flexibility, greater impulsivity, and anxious-like behavior, as well as higher rates of alcohol consumption. Furthermore, multiple G×E interactions have been documented for levels of 5-HIAA, hypothalamic–pituitary–adrenocortical (HPA) axis activity, alcohol consumption, rates of behavioral pathology, social play, aggression, and infant temperament. In most cases, these interactions were due to worse outcomes in l / s subjects that had been subjected to early maternal deprivation. This program of research demonstrates that l / s monkeys are more vulnerable to the effects of early-life stress, whereas l / l monkeys are more resilient.