Molecular Psychiatry (2005), 1–2
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SCIENTIFIC CORRESPONDENCE
Relationship of a 5-HT
transporter functional
polymorphism to 5-HT1A
receptor binding in healthy
women
Molecular Psychiatry advance online publication,
10 May 2005; doi:10.1038/sj.mp.4001680
SIR—Variations in the gene encoding the serotonin
transporter (5-HTT), which regulates reuptake of
brain serotonin (5-HT), are thought to affect the levels
of 5-HT in the brain. This study reports that LS/SS
variants of the human 5-HTT gene (SLC6A4) are
associated with increased 5-HT1A receptor binding in
cingulate brain regions in healthy women (HW).
A functional polymorphism in the promoter region
of the human 5-HTT gene (SLC6A4) has been
implicated in the modulation of mood and antidepressant response.1 Several lines of evidence show
that the genotype with two copies of the long
(L, 528 bp) allele leads to greater 5-HT reuptake
compared to genotypes having either one or two
copies of the short (S, 484 bp) allele.2 Since 5-HTT
regulates 5-HT concentrations in the synaptic cleft by
recycling released 5-HT, individuals with the S allele
are likely to have higher extracellular 5-HT concentrations during neurodevelopment and, possibly, in
the mature 5-HT system. The activity of the 5-HTT is
thought to influence the 5-HT1A receptor. For example, chronic administration of serotonin reuptake
inhibitors (SRIs) leads to a desensitization of 5-HT1A
autoreceptors.3 However, to our knowledge, no studies have investigated the relationship of this 5-HTT
polymorphism to 5-HT1A receptor binding in vivo in
healthy subjects.
In all, 16 HW were recruited as described previously.4 HW had no history of any psychiatric,
medical, or neurological illness and were not taking
any relevant medication. This study was conducted
according to local institutional review board regulations, and all subjects gave written informed consent.
PET imaging was performed during the first 10 days of
the follicular phase of the menstrual cycle. PET and
[carbonyl-11C]WAY100635 methods have been described previously.5 Dynamic PET scanning was
performed over a period of 60 or 90 min with arterial
blood sampling. The longer 90 min acquisition was
collected in 11 HW. For the arterial-based kinetic
analyses, regional [11C]WAY100635 distribution volume (DV) values were determined using a modified
Logan graphical method6 after smoothing of the data.
The Logan analysis was performed over 25–60 min
(seven points) and over 25–90 min (10 points) for the
60 and 90 min comparative analyses, respectively.
The specific binding potential (BP) measure was
determined as BP ¼ DVRegion of InterestDVCerebellum7 in
prefrontal, lateral and medial orbital frontal, cingulate, mesial and lateral temporal, and parietal cortices
as well as in the dorsal raphe.
S and L alleles were determined using DNA amplification (PCR) and established flanking primers. Amplification products were resolved by electrophoresis and
visualized with ethidium bromide staining and UV
transillumination, according to Edenberg and Reynolds.8
The 16 HW were 25.0 (SD 6.0) years old (range
18.6–39.9) and had a body mass index of 22.3 kg/m2
(SD 2.1) (range 18.7–26.3). High correlations were
observed between the cerebellar DV and regional BP
measures calculated using the 60 and 90 min data sets
(r ¼ 0.96–0.99), supporting the validity of the results
obtained using the 60 min data set. The sample
showed allele frequencies of 59% for the L allele
and 41% for the S allele with a genotype distribution
of 37.5% LL, 43.7% LS, and 18.8% SS, which is in
accordance with a larger predominantly North American–European population.9
Nonparametric methods (Wilcoxon’s rank-sum test)
showed a significant (Pr0.05) increase in [11C]WAY
100635 BP in pregenual (5.1771.06 vs 3.8671.19)
and subgenual cingulate (5.3371.15 vs 4.0470.88)
regions for the LS/SS genotypes compared to the LL
genotypes (Figure 1). The power related to each of
these findings is 0.71 and 0.84, respectively. There
were trends for similar differences for the orbital
frontal (5.1471.09 vs 4.0871.39; P ¼ 0.09) and the
lateral temporal (5.7671.36 vs 4.4871.04; P ¼ 0.09)
cortex. No differences were found for other regions,
including the raphe.
These data suggest that the LS/SS genotypes, which
presumably are associated with greater extracellular
5-HT concentrations, at least during early developmental periods, are associated with increased postsynaptic 5-HT1A receptor density in HW, as indexed
by [11C]WAY100635 BP, in subregions of the anterior
cingulate cortex, and possibly other cortical regions,
but not the raphe. Autoreceptor 5-HT1A activation is
thought to be a negative feedback mechanism that
reduces raphe activity.10 Recent studies show that
postsynaptic 5-HT1A receptors, in frontal regions,
have inhibitory properties through feedback loops
on raphe activity.11 Perhaps, increased activity of the
postsynaptic 5-HT1A receptor is part of the homeostatic mechanisms that serve to counterbalance
increased extracellular 5-HT concentrations in HW.
Alternatively, increased postsynaptic 5-HT1A availability may represent a homeostatic response to
reduced 5-HT tone resulting from developmental
changes (eg reduction of 5-HT fibers and/or raphe
firing12 associated with initially increased 5-HT
availability in 5-HTTLPR short allele carriers).
Scientific Correspondence
7.0
6.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
p =.04
LL
LS , SS
3.0
(11C)WAY 100635
BP dorsal raphe
7.0
(11C)WAY 100635 BP
pregenual cingulate
(11C)WAY 100635 BP
subgenual cingulate
2
5.0
4.0
3.0
2.0
1.0
0.0
2.0
1.0
p =.05
LL
p =.94
0.0
LS , SS
LL
LS , SS
11
Figure 1 Scatter histograms with mean and standard deviation of the [ C]WAY100635 BP values for LL and LS/SS
genotypes in the subgenual cingulate (left graph), the pregenual cingulate (middle graph), and the dorsal raphe (right graph)
of HW. Group comparisons by Wilcoxon’s rank-sum test with Exact Sig. presented.
We assessed the naturalistic relationships of genetic
variation presumably resulting in altered 5-HTT
availability. Experimental paradigms, which involve
massive manipulations of a homeostatic system in
animals, have different findings. 5-HTT knockout
mice show reduced density of 5-HT1A receptors in the
raphe, and some nuclei of the hypothalamus, amygdala, and septum.13 Rodents chronically treated with
SRIs14,15 have desensitization of 5-HT1A receptors in
the raphe and hypothalamus, but not the hippocampus or cortex. Together, these data suggest that 5-HT1A
receptor response is region specific and may also be
influenced by gender.13,16 5-HT1A receptors and the 5HTT are part of a complex 5-HT neuronal pathway
involving many other receptors, intracellular cascades, enzymes, and other components. It is likely
that different paradigms have different functional
effects on these many elements that contribute to
neuronal activity.
Finally, in support of these findings, others have
found that individuals with SS or LS genotypes
exhibit greater amygdala neuronal activity in response to salient stimuli, in comparison to individuals with LL genotype.17 It is possible that an
increase in 5-HT1A receptor density associated with
SS/LS genotype may inhibit function of the anterior
cingulate, a region that normally serves to inhibit
amygdala reactivity,18 thus contributing to heightened
amygdale response.
Acknowledgements
This work was supported by grants from NIMH
MH46001, MH42984, and K05-MD01894. UFB was
funded by an Erwin–Schrödinger Fellowship of the
Austrian Science Fund (Nos. J 2188 and J 2359-B02).
M Lee1, UF Bailer2,3, GK Frank2,4, SE Henry2,
CC Meltzer2,5,6, JC Price5, CA Mathis5, KT Putnam7,
RE Ferrell1, AR Hariri2 and WH Kaye2
Molecular Psychiatry
1
Department of Human Genetics, Graduate School of
Public Health, University of Pittsburgh, Pittsburgh, PA,
USA; 2Department of Psychiatry, Western Psychiatric
Institute and Clinic, School of Medicine, University of
Pittsburgh, Pittsburgh, PA, USA; 3Department of General
Psychiatry, Medical University of Vienna, University
Hospital of Psychiatry, Vienna, Austria; 4Department of
Child and Adolescent Psychiatry, School of Medicine,
University of California San Diego, La Jolla, CA, USA;
5
Department of Radiology, School of Medicine, University
of Pittsburgh, Presbyterian University Hospital, Pittsburgh,
PA, USA; 6Department of Neurology, School of Medicine,
University of Pittsburgh, Presbyterian University Hospital,
Pittsburgh, PA, USA; 7Department of Environmental
Health, Division of Epidemiology and Biostatistics,
University of Cincinnati, Cincinnati, OH, USA
Correspondence should be addressed to WH Kaye, MD,
University of Pittsburgh, School of Medicine, Department of
Psychiatry, Western Psychiatric Institute and Clinic, Iroquois
Building, Suite 600, 3811 O’Hara Street, Pittsburgh, PA 15213,
USA. E-Mail: kayewh@upmc.edu
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