Reduced sensitivity to both positive and negative reinforcement in mice over-expressing the 5-hydroxytryptamine transporter

The 5-hydroxytryptamine (5-HT) transporter (5-HTT) is believed to play a key role in both normal and pathological psychological states. Much previous data suggest that the s allele of the polymorphic regulatory region of the 5-HTT gene promoter is associated with reduced 5-HTT expression and vulnerability to psychiatric disorders, including anxiety and depression. In comparison, the l allele, which increases 5-HTT expression, is generally considered protective. However, recent data link this allele to both abnormal 5-HT signalling and psychopathic traits. Here, we studied the processing of aversive and rewarding cues in transgenic mice that over-express the 5-HTT (5-HTTOE mice). Compared with wild-type mice, 5-HTTOE mice froze less in response to both a tone that had previously been paired with footshock, and the conditioning context. In addition, on a decision-making T-maze task, 5-HTTOE mice displayed reduced preference for a larger, delayed reward and increased preference for a smaller, immediate reward, suggesting increased impulsiveness compared with wild-type mice. However, further inspection of the data revealed that 5-HTTOE mice displayed a relative insensitivity to reward magnitude, irrespective of delay. In contrast, 5-HTTOE mice appeared normal on tests of spatial working and reference memory, which required an absolute choice between options associated with either reward or no reward. Overall, the present findings suggest that 5-HTT over-expression results in a reduced sensitivity to both positive and negative reinforcers. Thus, these data show that increased 5-HTT expression has some maladaptive effects, supporting recent suggestions that l allele homozygosity may be a potential risk factor for disabling psychiatric traits.