The present findings that 5-HTTLPR allelic variations significantly alter the 5-HT1A
receptor system in the rhesus monkey are consistent with a similar study in humans (David et al.,2005
). In that retrospective human study, PET imaging of a 5-HT1A
antagonist radioligand in a total of 35 healthy individuals revealed carriers of the short 5HTTLPR genotypes exhibited decreased 5-HT1A
binding throughout 5-HT1A
expressing regions of the brain. As with our results, this decrease in binding was seen in all cortical brain regions as well as the raphe midbrain region. A more recent study in humans (n=54), however, did not find an 5-HTTLPR association with 5-HT1A
binding (Borg et al.,2009
). Both these human studies describe similar methods, using [C-11]WAY100635 in middle age subjects. However, the study with negative findings reported a much higher variation in 5-HT1A
binding across the subjects (~2-fold greater c.o.v.) suggesting a more heterogeneous population or some unknown source of variance. It is also possible different processing methodologies might have contributed to large variabilities across subjects.
Radioligand imaging studies of 5-HTT binding in 5-HTTLPR variants have reported a metric of “binding potential” representing an index proportional to the receptor density (Bmax) and ligand-protein affinity (1/KDapp). Using this composite index, potential decreases in receptor density could be masked by matching increases in affinity, or accompanying decreases in endogenous 5-HT competition. With this limitation, the interpretation of the decreased 5-HT1A binding reported in s-carriers could be due to either elevated 5-HT tone or 5-HT1A downregulation. Additional studies and methodologies interrogating 5-HT function, such as measurements separating receptor density from affinity in pre- and post-synaptic receptors and 5-HT metabolism, will be required to understand the role of the 5-HTT and the mechanisms by which this decrease in 5-HT1A binding was achieved.
The rhesus 5-HTTLPR length polymorphism has been used extensively to study neurobehavioral functioning. Research on resiliency to stressful events or conditions in infant and juvenile rhesus monkeys has shown that carriers of the short allele demonstrate heightened physical aggression and HPA response, altered serotonin metabolism and regional brain metabolism (Bennett et al.,2002
;Barr et al.,2004b
;Champoux et al.,2002
;Kalin et al.,2008
;Barr et al.,2003
), illustrating the strength of the rhesus monkey model for the study of gene × environment interactions (Suomi,2006
). Previous work from our lab using subjects included with the research reported herein found that prenatal alcohol-exposed carriers of the s-allele exhibited increased neonatal irritability and increased stress responses compared to l/l
homozygotes independent of prenatal alcohol exposure (Kraemer et al.,2008
). The statistical model for the present research included treatment groups to account for potential prenatal condition alterations, permitting us to focus on the effect of 5-HTTLPR allelic variations over and above any prenatal treatment main effects. We regard this research as a first step in understanding the effects of 5-HTTLPR variations on 5-HT function in the rhesus monkey model. Future analysis of this cohort will examine interactions between 5HTTLPR, 5-HT1A and prenatal treatment with behavioral measures.
A recent study from another lab evaluated 5-HT1A
binding in rhesus monkeys as a function of 5-HTTLPR length polymorphisms, among other biomarker comparisons. Using a smaller sample size (n=8) of all male subjects, Jedema and colleagues found no statistically significant difference in 5-HT1A
binding between s-carriers and (l/l
) homozygotes (Jedema et al.,2010
). However, consistent with our results, reduced 5-HT1A
binding was observed in all reported cortical and midbrain regions (p < 0.116 using multivariate analysis). As suggested by the authors, their study may have been underpowered for detecting the allelic group differences. In our study, there was a 7% difference between groups when averaged over all regions of the 58 subjects. Using MRI T1 images of their cohort, Jedema et al. found statistically significant differences in cortical morphology in regional gray matter volume, with s-carriers having reduced volume in several brain regions that were implicated in measured cognitive tasks. A limitation of the present study is that we do not have MRI images available on this cohort. Therefore, it is conceivable that a thinner cortex in s-carriers would result in lower measured 5-HT1A
binding due to image resolution (i.e. partial volume) effects even if 5-HT1A
receptor density was preserved. To address this, in part, the PET DVR images were spatially smoothed after transforming to atlas space to minimize the variability of imperfect ROI placement over peak DVR values. Further, all cortical volumes consisted of large regional sampling resulting in lower [F-18]mefway DVR values when compared to our previously published values using [F-18]mefway (Wooten et al.,2011
) and perhaps masking large differences in 5-HT1A
binding in focal brain regions.
In conclusion, carriers of the 5-HTTLPR short allele were found to have significantly reduced binding at the 5-HT1A
receptor sites, suggesting that 5-HTTLPR length variations play a role in the regulation of the 5-HT system. The rhesus model was used to provide a study cohort that minimizes variability potentially affecting the 5-HT system which is found in the human population, including psychosocial stress and substance abuse. These findings also confirm that 5-HT related alterations persist into adulthood, given the age of the rhesus subjects (14.5 yrs) were approximately equivalent to humans in their fourth decade of life, an age similar that of the study by David and colleagues in humans (David et al.,2005
). An intriguing question is that of the developmental course of differences in 5-HT function between 5-HTTLPR variants and the possibility of developmentally vulnerable periods of 5-HT disruption.