In this study, we demonstrated a robust association between in vivo regional reductions in [11C]P943 BPND, a measure of serotonin type 1B receptor expression, and trauma history in patients with PTSD and in TC participants. Lower [11C]P943 BPND in PTSD was associated with an earlier age at first trauma exposure, a greater number of lifetime trauma exposures, more severe PTSD symptoms, and comorbidity with MDD. Regression analyses clarified that participant age at onset of the first trauma was the strongest predictor of [11C]P943 BPND reductions in individuals with a history of severe trauma.
The findings that low serotonin type 1B receptor expression is associated with greater symptom severity, co-morbidity with MDD, earlier onset of trauma exposure, and greater total lifetime trauma burden are consistent with the results of numerous epidemiologic studies documenting elevated risk of PTSD and more severe symptoms associated with childhood trauma and higher trauma load.5–9,43
In particular, early life stress has been repeatedly implicated as a risk factor for adult trauma exposure56,57
and for the development of PTSD.7,58,59
Although most research has focused on neuroendocrine function and the hypothalamic-pituitary-adrenal axis as mediating biological factors between early trauma and risk of PTSD,43,60
the findings of the present study highlight the serotonin system as being potentially important as well. The present findings are consistent with the lasting behavioral effects resulting from early perturbations of the serotonin system leading to anxiety-related phenotypes in animals.61,62
The strong association between trauma exposure and reduced serotonin type 1B receptor level found in the trauma control group further demonstrates the specific effects of trauma on molecular adaptations in neuronal networks that are dysfunctional in PTSD. However, low [11C]P943 BPND in the PTSD and TC groups suggests that abnormal serotonin type 1B receptor expression does not sufficiently explain the phenotype of PTSD. Thus, the data more strongly support the hypothesis that the extent of serotonin type 1B receptor alteration reflects features of trauma exposure (eg, age at exposure and the intensity, number, or perhaps other features of the trauma history) rather than the nature of the response to the trauma (eg, whether the individual did or did not develop PTSD). Individuals who proceed to develop PTSD would be expected to possess an additional vulnerability factor resulting from genetic or environmental factors or to lack a protective factor that may characterize resistance to the pathologic effects of trauma.
Autoradiographic studies demonstrate high levels of serotonin type 1B receptors localized to the basal ganglia,27,63–66
with somewhat lower levels localized to the neocortex and the amygdala,27,67
consistent with the findings of the present study. The observed [11
reductions in the trauma-exposed cohorts were in the amygdala, the ACC, and the caudate, in line with current neurocircuitry hypotheses of PTSD.36,39,40
The largest [11
reductions were in the caudate, a region that has been implicated in normal emotional behavior and emotional disorders68–70
; however, it has received relatively little attention in neurobiological studies of PTSD (although several studies71–74
do address it). Of note, Cohen et al73
reported volumetric reductions in the caudate and the ACC in adults with a history of high levels of early life stress in the absence of psychiatric illness. The researchers found that higher levels of childhood and adolescent stress were associated with a larger magnitude of volumetric reduction, paralleling the findings of the present study. However, the [11
data reported in the present study are corrected for any volumetric variation in the sample so that our serotonin type 1B receptor findings represent an additional neurobiological abnormality rather than being explained by any potential volumetric variations.
Functionally, serotonin type 1B receptors are G proteins negatively coupled to adenylyl cyclase that seem to regulate limbic corticostriatal signaling primarily as axon terminal heteroreceptors on nonserotonergic neurons (eg, γ-aminobutyric acid–, glutamate-, and dopamine-containing neurons).75–78
Although the behavioral functions of this receptor are incompletely understood, numerous preclinical studies30–35,79–81
implicate the receptor in emotional behavior, stress reactivity, and anxiety states. The present findings of in vivo reductions in serotonin type 1B receptors associated with trauma are consistent with those of animal studies34,35
demonstrating reductions in serotonin type 1B receptor messenger RNA transcription after stress exposure. A study33
of serotonin type 1B receptor overexpression in the dorsal raphe nucleus demonstrates decreased anxiety in animals (ie, fear-potentiated startle) in a stress-dependent manner. Loss of serotonin type 1B receptor–mediated regulation of glutamate and γ-aminobutyric acid systems has the potential to lead to downstream reductions in neurotrophic signaling and neurogenesis and loss of dendritic spines and branches in neurocircuitry relevant to PTSD.82
The serotonin system likely plays a role in multiple psychiatric disorders, and the degree of specificity of the observed [11
reductions related to trauma exposure in the present study remains uncertain. Some of us recently reported reduced ventral striatal [11
in individuals with MDD compared with HC participants.83
In a second study,84
some of us found elevated ventral striatal [11
in individuals with alcohol dependence. Notably, MDD and alcohol dependence are often comorbid with PTSD. However, no ventral striatal between-group differences were observed in the present study. Instead, we found reduced [11
in the caudate in trauma-exposed individuals. Although the causative implications of these differential binding patterns are not yet fully understood, these initial data suggest potential diagnostic specificity.
Some difficulty can occur in interpreting BPND
data from human neuroimaging studies. Between-group differences in ligand binding could represent differences in receptor number as a result of true downregulation, which requires receptor degradation and perhaps decreased synthesis. Alternately, increased serotonin release, enhanced neuronal activity in the dorsal raphe nuclei, and increased serotonin synthesis and turnover in response to stress85,86
could lead to agonist-induced internalization of serotonin type 1B receptors.87
Finally, assuming a displacement model, differences in ligand binding could be explained by changes in transmitter release in which serotonin and the radioligand may compete directly for occupancy of the same receptor binding site,88
although this possibility has not yet been sufficiently addressed in human studies.
Several limitations to the present study deserve comment. Inherent limitations exist regarding the reliance on retrospective participant reports of trauma history. We also chose to include a broad range of trauma histories and individuals who had experienced multiple different trauma types. Therefore, the specific contribution of different types of trauma cannot be evaluated reliably in this study owing to the presence of multiple traumas of mixed types in many individuals in the cohort. However, the inclusion of a range of trauma histories allowed for observations of correlations between the developmental timing of trauma, trauma load, and serotonin type 1B receptor measures. The present study design does not address the important question of whether trauma exposure directly reduces serotonin type 1B receptor expression. Preclinical data suggest serotonin type 1B receptor modulation by environmental stress. However, other explanations for the observed findings include premorbid low levels of serotonin type 1B receptor expression resulting from genetic or environmental factors in individuals predisposed to trauma exposure or to the development of PTSD. Perhaps most important, this study did not allow us to fully clarify the potential pathologic role of reduced serotonin type 1B receptor expression in PTSD.
The findings of the present study are consistent with the premise that exposure to early trauma produces long-lasting neurobiological changes in the human brain and suggests a potential neurodevelopmental component in the cause of PTSD. Future studies are needed to clarify molecular factors in addition to the serotonin type 1B receptor that may characterize individuals who are vulnerable to the potentially pathogenic effects of trauma.