title: Dopaminergic involvement during mental fatigue in health and cocaine addiction.
abstract: Dopamine modulates executive function, including sustaining cognitive control during mental fatigue. Using event-related functional magnetic resonance imaging (fMRI) during the color-word Stroop task, we aimed to model mental fatigue with repeated task exposures in 33 cocaine abusers and 20 healthy controls. During such mental fatigue (indicated by increased errors, and decreased post-error slowing and dorsal anterior cingulate response to error as a function of time-on-task), healthy individuals showed increased activity in the dopaminergic midbrain to error. Cocaine abusers, characterized by disrupted dopamine neurotransmission, showed an opposite pattern of response. This midbrain fMRI activity with repetition was further correlated with objective indices of endogenous motivation in all subjects: a state measure (task reaction time) and a trait measure (dopamine D2 receptor availability in caudate, as revealed by positron emission tomography data collected in a subset of this sample, which directly points to a contribution of dopamine to these results). In a second sample of 14 cocaine abusers and 15 controls, administration of an indirect dopamine agonist, methylphenidate, reversed these midbrain responses in both groups, possibly indicating normalization of response in cocaine abusers because of restoration of dopamine signaling but degradation of response in healthy controls owing to excessive dopamine signaling. Together, these multimodal imaging findings suggest a novel involvement of the dopaminergic midbrain in sustaining motivation during fatigue. This region might provide a useful target for strengthening self-control and/or endogenous motivation in addiction.
authors.affiliation: Department of Medical Research, Center for Translational Neuroimaging, Brookhaven National Laboratory, Upton, NY 11973-5000, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Moeller
authors.forename: D
authors.initials: D
authors.lastname: Tomasi
authors.forename: J
authors.initials: J
authors.lastname: Honorio
authors.forename: N D
authors.initials: ND
authors.lastname: Volkow
authors.forename: R Z
authors.initials: RZ
authors.lastname: Goldstein
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D016022:Case-Control Studies; D002421:Caudate Nucleus / Q000378:metabolism / Q000503:physiopathology; D019970:Cocaine-Related Disorders / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D056344:Executive Function; D005260:Female; D059907:Functional Neuroimaging; D006179:Gyrus Cinguli / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D005222:Mental Fatigue / Q000378:metabolism* / Q000503:physiopathology; D008774:Methylphenidate / Q000494:pharmacology; D008875:Middle Aged; D009042:Motivation; D049268:Positron-Emission Tomography; D011930:Reaction Time; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D057190:Stroop Test; D013378:Substantia Nigra / Q000378:metabolism / Q000503:physiopathology; D013681:Tegmentum Mesencephali / Q000378:metabolism / Q000503:physiopathology; D017557:Ventral Tegmental Area / Q000378:metabolism / Q000503:physiopathology
chemical_list: D018765:Dopamine Uptake Inhibitors; D017448:Receptors, Dopamine D2; D008774:Methylphenidate