title: Frontal Traumatic Brain Injury in Rats Causes Long-Lasting Impairments in Impulse Control That Are Differentially Sensitive to Pharmacotherapeutics and Associated with Chronic Neuroinflammation.
abstract: Traumatic brain injury (TBI) affects millions yearly, and is increasingly associated with chronic neuropsychiatric symptoms. We assessed the long-term effects of different bilateral frontal controlled cortical impact injury severities (mild, moderate, and severe) on the five-choice serial reaction time task, a paradigm with relatively independent measurements of attention, motor impulsivity, and motivation. Moderately- and severely injured animals exhibited impairments across all cognitive domains that were still evident 14 weeks postinjury, while mild-injured animals only demonstrated persistent deficits in impulse control. However, recovery of function varied considerably between subjects such that some showed no impairment ("TBI-resilient"), some demonstrated initial deficits that recovered ("TBI-vulnerable"), and some never recovered ("chronically-impaired"). Three clinically relevant treatments for impulse-control or TBI, amphetamine, atomoxetine, and amantadine, were assessed for efficacy in treating injury-induced deficits. Susceptibility to TBI affected the response to pharmacological challenge with amphetamine. Whereas sham and TBI-resilient animals showed characteristic impairments in impulse control at higher doses, amphetamine had the opposite effect in chronically impaired rats, improving task performance. In contrast, atomoxetine and amantadine reduced premature responding but increased omissions, suggesting psychomotor slowing. Analysis of brain tissue revealed that generalized neuroinflammation was associated with impulsivity even when accounting for the degree of brain damage. This is one of the first studies to characterize psychiatric-like symptoms in experimental TBI. Our data highlight the importance of testing pharmacotherapies in TBI models in order to predict efficacy, and suggest that neuroinflammation may represent a treatment target for impulse control problems following injury.
authors.forename: Cole
authors.initials: C
authors.lastname: Vonder Haar
authors.forename: Frederick C W
authors.initials: FC
authors.lastname: Lam
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Adams
authors.affiliation: Brain and Spinal Injury Center, Departments of Physical Therapy Rehabilitation Science and Neurological Surgery, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Lara-Kirstie
authors.initials: LK
authors.lastname: Riparip
authors.forename: Sukhbir
authors.initials: S
authors.lastname: Kaur
authors.forename: Michael
authors.initials: M
authors.lastname: Muthukrishna
authors.affiliation: Brain and Spinal Injury Center, Departments of Physical Therapy Rehabilitation Science and Neurological Surgery, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Susanna
authors.initials: S
authors.lastname: Rosi
authors.forename: Catharine A
authors.initials: CA
authors.lastname: Winstanley
mesh_terms: D000208:Acute Disease; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000547:Amantadine / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000069445:Atomoxetine Hydrochloride / Q000494:pharmacology; D000070642:Brain Injuries, Traumatic / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology* / Q000523:psychology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D007174:Disruptive, Impulse Control, and Conduct Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D015259:Dopamine Agents / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000276:immunology / Q000293:injuries* / Q000473:pathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D020318:Rats, Long-Evans; D012720:Severity of Illness Index
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D000069445:Atomoxetine Hydrochloride; D000547:Amantadine; D000661:Amphetamine
keywords: Controlled cortical impact; amphetamine; cytokine; impulsivity; prelimbic