title: 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.
authors.affiliation: Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, MD 20852-9411, USA. brigmanj@mail.nih.gov
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Brigman
authors.forename: Poonam
authors.initials: P
authors.lastname: Mathur
authors.forename: Judith
authors.initials: J
authors.lastname: Harvey-White
authors.forename: Alicia
authors.initials: A
authors.lastname: Izquierdo
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Saksida
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Bussey
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fox
authors.forename: Evan
authors.initials: E
authors.lastname: Deneris
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Murphy
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics; D010134:Fenclonine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology*; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D010134:Fenclonine; D005473:Fluoxetine; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse