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


METHODS
Sixty-three patients with severe TBI (Glasgow Coma Scale score < or = 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).


CONCLUSIONS
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.
Wagner
Amy K
AK
Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pennsylvania 15213, USA. wagnerak@upmc.edu
Ren
Dianxu
D
Conley
Yvette P
YP
Ma
Xiecheng
X
Kerr
Mary E
ME
Zafonte
Ross D
RD
Puccio
Ava M
AM
Marion
Donald W
DW
Dixon
C Edward
CE
D015102:3,4-Dihydroxyphenylacetic Acid / Q000134:cerebrospinal fluid*; D000328:Adult; D001930:Brain Injuries / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000628:therapy; D004298:Dopamine / Q000134:cerebrospinal fluid*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D005838:Genotype; D015600:Glasgow Coma Scale; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid*; D006801:Humans; D008297:Male; D012737:Sex Factors; D013997:Time Factors
D050483:Dopamine Plasma Membrane Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine; D006719:Homovanillic Acid