The serotonin transporter knock-out rat: A review

ABSTRACT This chapter dicusses the most recent data on the serotonin transporter knock-out rat, a unique rat model that has been generated by target-selected N-ethyl-N-nitrosourea (ENU) driven mutagenesis. The knock-out rat is the result of a premature stopcodon in the serotonin transporter gene, and the absence of the serotonin transporter has been confirmed at mRNA, protein, and functional levels. The serotonin transporter (SERT) plays a crucial role in serotonin reuptake and its absence has a huge effect on serotonin neurotransmission - exemplified by increased extracellular serotonin levels, reduced serotonin tissue/platelet/blood levels, and reduced evoked serotonin release - yet the animals appear normal and do not differ from wildtype littermates in respect to breeding and health. Behavioral phenotypes are only apparent when the animals are exposed to certain stimuli. For instance, the serotonin transporter knock-out rat displays increased stress sensitivity in a variety of anxiety- and depression-like tests, such as the elevated plus maze test and the forced swim test. Also remarkable, while general activity is not changed, the knock-out rats show a “neurotic-like” exploratory pattern. In line with the serotonin hypothesis of impulsivity, which argues that there is an inverse relationship between the two, serotonin transporter knock-out rats show reduced motor impulsivity in the five-choice serial reaction time task, and a reduction in social interaction during play and aggressive encounters. Interestingly, abdominal fat seems to be increased in the knock-out rat, despite normal body weight. Pharmacological compounds also elicit genotype-dependent responses in the knock-out rats.