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

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.

Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes

“…Beginning 1 day after conditioning, mice were provided with 120 mg/l FLX hydrochloride (LKT Laboratories, St Paul, MN) in (their only source of) drinking water, as previously described (Brigman et al, 2010). This concentration was chosen based on previous data from our laboratory to attain an average self-administered daily dose of B10 mg/kg.…”

Fluoxetine (Prozac) and Serotonin Act on Excitatory Synaptic Transmission to Suppress Single Layer 2/3 Pyramidal Neuron-Triggered Cell Assemblies in the Human Prefrontal Cortex

“…Humans (Harmer et al, 2003;Schmitt et al, 2006) and animals (Clarke et al, 2004;Brigman et al, 2010) display altered cognitive performance after having their central 5-HT level experimentally manipulated. With limited studies performed on human pyramidal cells (McCormick and Williamson, 1989;Newberry et al, 1999), our current knowledge about synaptic mechanisms of 5-HT in the cortex is based on non-human in vitro experiments in which micromolar concentrations of 5-HT were applied (Andrade and Nicoll, 1987;Aghajanian and Marek, 1997;Schmitz et al, 1998b;Ciranna, 2006;Zhong et al, 2008).…”

Behavioural therapy based on distraction alleviates impaired fear extinction in male serotonin transporter knockout rats

“…9,10 In the present study, we used 5-HTT -/-rats, which are well accepted as a model for the 5-HTTLPR s-allele, 3,11 to test our prediction, and we designed a "distraction" therapy in which the fear-eliciting stimulus was copresented with a sucrose pellet-predicting stimulus during fear extinction.…”