Pharmacological or Genetic Inactivation of the Serotonin Transporter Improves Reversal Learning in Mice

TLDR

Cortical serotonin is increasingly recognized as a key modulator of cognitive flexibility, yet its precise role and genetic influences remain unclear. The study employed a touch‑screen operant reversal task, comparing reversal performance in 5‑HTT knockout and fluoxetine‑treated mice, as well as in Pet‑1 knockout and PCPA‑treated mice. Both fluoxetine‑treated and 5‑HTT knockout mice committed fewer errors early in reversal, whereas Pet‑1 knockout and PCPA‑treated mice showed no improvement, indicating that 5‑HTT inactivation enhances reversal learning and highlighting potential therapeutic targets for cognitive inflexibility.

Abstract

Growing evidence supports a major contribution of cortical serotonin (5-hydroxytryptamine, 5-HT) to the modulation of cognitive flexibility and the cognitive inflexibility evident in neuropsychiatric disorders. The precise role of 5-HT and the influence of 5-HT gene variation in mediating this process is not fully understood. Using a touch screen–based operant system, we assessed reversal of a pairwise visual discrimination as an assay for cognitive flexibility. Effects of constitutive genetic or pharmacological inactivation of the 5-HT transporter (5-HTT) on reversal were examined by testing 5-HTT null mice and chronic fluoxetine-treated C57BL/6J mice, respectively. Effects of constitutive genetic loss or acute pharmacological depletion of 5-HT were assessed by testing Pet-1 null mice and para-chlorophenylalanine (PCPA)–treated C57BL/6J mice, respectively. Fluoxetine-treated C57BL/6J mice made fewer errors than controls during the early phase of reversal when perseverative behavior is relatively high. 5-HTT null mice made fewer errors than controls in completing the reversal task. However, reversal in Pet-1 null and PCPA-treated C57BL/6J mice was not different from controls. These data further support an important role for 5-HT in modulating reversal learning and provide novel evidence that inactivating the 5-HTT improves this process. These findings could have important implications for understanding and treating cognitive inflexibility in neuropsychiatric disease.