title: MPTP-induced executive dysfunction is associated with altered prefrontal serotonergic function.
abstract: In Parkinson's disease, cognitive deficits manifest as fronto-striatally-mediated executive dysfunction, with impaired attention, planning, judgment, and impulse control. We examined changes in executive function in mice lesioned with subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using a 3-choice serial reaction-time (SRT) task, which included measures of sustained attention and impulse control. Each trial of the baseline SRT task comprised a pseudo-random pre-cue period ranging from 3 to 8 s, followed by a 1-s cue duration. MPTP impaired all measures of impulsive behavior acutely, but with additional training their performance normalized to saline control levels. When challenged with shorter cue durations, MPTP-lesioned mice had significantly slower reaction times than wild-type mice. When challenged with longer pre-cue times, the MPTP-lesioned mice exhibited a loss of impulse control at the longer durations. In lesioned mice, striatal dopamine was depleted by 54% and the number of tyrosine-hydroxylase-positive neurons in the substantia nigra pars compacta was reduced by 75%. Serotonin (5-HT) was unchanged in the striatum and prefrontal cortex (PFC), but the ratio of 5-hydroxyindolacetic acid (5-HIAA) to 5-HT was significantly reduced in the MPTP group in the PFC. In lesioned mice, prefrontal 5-HIAA/5-HT was significantly correlated with the executive impairments and striatal norepinephrine was associated with slower reaction times. None of the neurochemical measures was significantly associated with behavior in saline-treated controls. Taken together, these results show that prefrontal 5-HT turnover may play a pivotal role in MPTP-induced executive dysfunction.
authors.affiliation: Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Panchanan
authors.initials: P
authors.lastname: Maiti
authors.affiliation: Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Gregg
authors.affiliation: Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, United States. Electronic address: mike@tennessee.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: McDonald
mesh_terms: D000818:Animals; D001288:Attention / Q000502:physiology; D003342:Corpus Striatum / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D056344:Executive Function / Q000502:physiology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007175:Impulsive Behavior / Q000502:physiology; D020267:MPTP Poisoning / Q000503:physiopathology* / Q000523:psychology*; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology; D009483:Neuropsychological Tests; D065842:Pars Compacta / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000503:physiopathology*; D011930:Reaction Time / Q000502:physiology; D012701:Serotonin / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Executive function; Impulse control; MPTP; Mice; Parkinson’s disease; Sustained attention