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200 Biobehavioral Resilience to Stress

neuronal terminals switch from a state of low activity to one of increased TH
activity in response to behavioral demand (Miner et al., 2006). Moreover, this
increased TH expression demonstrates considerable variability among sub-
jects, suggesting the possibility that there is a genetic variation.
Neuroendocrine, pharmacologic, and brain imaging studies provide
compelling evidence for a persistent increase in noradrenergic activity in
human subjects with PTSD. This increase is generally not observable under

baseline or resting conditions, but is readily observable in response to a vari-
ety of stressors (see review by Southwick et al., 1999). Measurement of nor-

epinephrine (NE) concentrations in cerebrospinal fluid under resting (basal)
conditions does provide direct evidence of persistent central hyperarousal

in PTSD. Like those who suffer from melancholic depression, individuals
with PTSD demonstrate increased concentrations of cerebrospinal fl uid NE
(Geracioti, Jr. et al., 2001; Wong et al., 2000). Moreover, NE concentrations in
subjects with PTSD correlate strongly with PTSD symptom levels (Geracioti
et al., 2001).
Certainly, there are many other pharmacologic compounds and relevant
genes that can and should be investigated with respect to PTSD and by refer-

ence to findings in the fi elds of pharmacology and neuroscience. Candidate
compounds and genes of particular interest are those that influence the sero-

tonergic, dopaminergic, noradrenergic, and CRF systems.

Conclusions and Recommendations

PTSD and resilience to PTSD are complex, multifactorial phenotypes whose

genetic and environmental influences are likely to be difficult to identify with

any single research paradigm. Thus, for example, association studies, espe-

cially those pursued on a genome-wide scale, will need replication in order to
provide compelling results. In addition, in order for any gene that might be
found to be associated with PTSD risk or resilience to play a convincing role
in the etiology of PTSD-related phenotypes, its biological role in mediating
PTSD must be characterized. Characterization of the “functional” role that
genes play with respect to human physiology is not trivial and requires the use

of state-of-the-field molecular and subclinical phenotyping technologies. In

addition, model species studies—which are often used to interrogate the func-
tional effects of genes via knockout, transgenic, and gene expression manipu-

lations—are not likely to reveal all relevant and important details about the
evolutionarily unique neural circuitry and genetic networks of relevance in

human subjects. Thus, the most logical and compelling option is to apply an

integrated approach by which the results of different studies and methodolo-
gies can be used to inform and confirm the results of one another.

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