Sex and genetic associations with cerebrospinal fluid dopamine and metabolite production after severe traumatic brain injury

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Dopamine (DA) pathways have been implicated in cognitive deficits after traumatic brain injury (TBI). Both sex and the dopamine transporter (DAT) 3′ variable number of tandem repeat polymorphism have been associated with differences in DAT protein density, and DAT protein affects both presynaptic DA release, through reverse transport, and DA reuptake. Catecholamines and associated metabolites are subject to autooxidation, resulting in the formation of reactive oxygen species that may contribute to subsequent oxidative injury. The purpose of this study was to determine associations between factors that affect DAT expression and cerebrospinal fluid (CSF) DA and metabolite levels after severe TBI.


Sixty-three patients with severe TBI (Glasgow Coma Scale score ≤ 8) were evaluated. The patients' genotypes were obtained using previously banked samples of CSF, and serial CSF samples (416 samples) were used to evaluate DA and metabolite levels. High-performance liquid chromatography was used to determine CSF levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) during the first 5 days after injury.

Mixed-effects multivariate regression modeling revealed that patients with the DAT 10/10 genotype had higher CSF DA levels than patients with either the DAT 9/9 or DAT 9/10 genotypes (p = 0.009). Females with the DAT 10/10 genotype had higher CSF DA levels than females with the DAT 9/9 or DAT 9/10 genotypes, and sex was associated with higher DOPAC levels (p = 0.004). Inotrope administration also contributed to higher DA levels (p = 0.002).


In addition to systemic administration of DA, inherent factors such as sex and DAT genotype affect post-TBI CSF DA and DA metabolite levels, a phenomenon that may modulate susceptibility to DA-mediated oxidative injury.

Abbreviations used in this paper:CBF = cerebral blood flow; COMT = catechol-O-methyltransferase; CPP = cerebral perfusion pressure; CSF = cerebrospinal fluid; CT = computed tomography; DA = dopamine; DAT = DA transporter; DOPAC = 3,4-dihydroxy-phenylacetic acid; EVD = extraventricular drain; GCS = Glasgow Coma Scale; HPLC = high-performance liquid chromatography; HVA = homovanillic acid; ICP = intracranial pressure; MAO = monoamine oxidase; PCR = polymerase chain reaction; SEM = standard error of the mean; TBI = traumatic brain injury; VNTR = variable number tandem repeat.

Article Information

Address reprint requests to: Amy K. Wagner, M.D., Department of Physical Medicine and Rehabilitation, University of Pittsburgh, 3471 Fifth Avenue, Suite No. 202, Pittsburgh, Pennsylvania 15213. email:

© AANS, except where prohibited by US copyright law.



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    Bar graphs demonstrating the adjusted mean values from the multivariate analysis of DA by time after severe TBI (upper) and by treatment and systemic administration of inotropes (lower) (*p < 0.05, compared with both Day 1 values [upper] and values with systemic administration of inotropes [lower]). DA_No = no inotrope administration; DA_Yes = inotrope administration.

  • View in gallery

    Graph depicting the adjusted mean values from the multivariate analysis of DA by sex and genotype (*p < 0.05, compared with values for females with the DAT 10/10 genotype).

  • View in gallery

    Bar graphs showing the adjusted mean values from the multivariate analysis of DOPAC by time after severe TBI (upper) and by sex, treatment, genotype, and systemic administration of inotropes (lower) (*p < 0.05, compared with values for females and values with hypothermia treatment).

  • View in gallery

    Graphs illustrating the adjusted mean values from the multivariate analysis of HVA by time after severe TBI (upper) and by sex, treatment, genotype, and systemic administration of ino-tropes (lower) (*p < 0.05, compared with Day 1 values).

  • View in gallery

    Bar graphs depicting the adjusted mean values from the multivariate analysis of the ratio of DOPAC to DA by time after severe TBI (upper) and by sex, treatment, genotype, and systemic administration of inotropes (lower) (*p < 0.05, compared with both Day 1 values [upper] and values with no systemic administration of inotropes [lower]).

  • View in gallery

    Graphs demonstrating the adjusted mean values from the multivariate analysis of the ratio of HVA to DA by time after severe TBI (upper) and by sex, treatment, genotype, and systematic administration of inotropes (lower) (*p < 0.05, compared with values for patients with the DAT 9/9 and DAT 9/10 genotypes and values with no systemic administration of inotropes).



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