5-HTTLPR status predictive of neocortical 5-HT4 binding assessed with [11C]SB207145 PET in humans
Highlights
► We evaluate if the 5-HTTLPR variant predicts serotonin 4 receptor (5-HT4) binding. ► We assess 5-HT4 binding with [11C]SB207145 PET in 47 healthy human volunteers. ► 5-HTTLPR status significantly predicts neocortical [11C]SB207145 binding. ► S allele carriers show 9% reduced binding across neocortex versus LL homozygotes. ► This further suggests that 5-HTTLPR affects 5-HT neurotransmission in adult humans.
Introduction
Serotonin (5-hydroxytryptamine, 5-HT) is a neuromodulator with significant effects on emotional behavior, including anxiety and sensitivity to threat (Blier and de Montigny, 1998, Lucki, 1998). Genetic polymorphisms that putatively affect serotonin signaling have been associated with affective disorders (e.g., depression and anxiety disorders) and aspects of personality that confer risk for these disorders (Caspi et al., 2003, Fakra et al., 2009, Lemonde et al., 2003, Wankerl et al., 2010). A clearer understanding of how these genetic variants modulate aspects of serotonin signaling is critical for leveraging that genetic information to model underlying brain chemistry and brain function. In turn, this knowledge can be used to identify how underlying serotonin signaling and its effects on brain function may contribute to variability in personality and risk for affective disorders (Hariri, 2009). Imaging genetics using neuroreceptor binding positron emission tomography (PET) has emerged as an approach for evaluating the impact of genetic variants on molecular mechanisms in humans, in vivo. The 5-HTTLPR is a common genetic variant within the gene (SLC6A4) coding for the serotonin transporter (5-HTT) where the ‘long’ (L) allele exhibits increased serotonin transporter (5-HTT) transcription in vitro relative to the ‘short’ (S) allele, putatively affecting 5-HT signaling (Lesch et al., 1996). As discussed within a recent review of genetic sources of variability in serotonin signaling as measured with PET, there is evidence suggesting that 5-HTTLPR status is associated with individual differences in aspects of serotonin signaling (Willeit and Praschak-Rieder, 2010).
Previous studies have reported reduced 5-HTT binding in S carriers with the PET radioligand [11C]DASB(Kalbitzer et al., 2009, Praschak-Rieder et al., 2007, Reimold et al., 2007), though other studies, including one using the PET radioligand [11C]McN5652, have reported no relation (Murthy et al., 2010, Parsey et al., 2006a). Additionally, the 5-HTTLPR S allele has been associated with decreased 5-HT type 1A receptor (5-HT1A) binding (David et al., 2005), though other studies have reported no relation (Borg et al., 2009). Recent studies also suggest that genetic variation putatively modulating 5-HT signaling may moderate the effect of environmental factors on 5-HT signaling, such as seasonal variation (Kalbitzer et al., 2010). This is consistent with a growing corpus of research suggesting that consideration of environmental triggers may be integral for identifying the impact of serotonin-related genetic variants on brain chemistry and related effects on behavior (Caspi et al., 2010). Though numerous studies have applied imaging genetics to identify serotonergic mechanisms modulated by common genetic polymorphisms, their effect on serotonin signaling is not fully understood (Willeit and Praschak-Rieder, 2010). Notably, identifying genetic sources of variability in serotonin signaling is limited by the capacity to effectively quantify it in vivo with PET (Paterson et al., 2010).
Recently, our lab has validated the quantitative use of a novel radioligand, [11C]SB207145, for measuring 5-HT type 4 receptor (5-HT4) binding with PET in humans (Marner et al., 2009, Marner et al., 2010). Recent animal studies have reported that cerebral 5-HT4 binding shows a monotonic response to pharmacologically induced changes in cerebral 5-HT levels, at least when exposure had lasted 2–3 weeks (Licht et al., 2009, Vidal et al., 2009). Furthermore, genetically modified expression of the gene coding for the 5-HTT induced significant alterations in 5-HT4 density in mice (Jennings et al., 2011). Specifically, mice over-expressing 5-HTT (i.e., resulting in reduced 5-HT signaling) showed increased 5-HT4 density while knock-out of the gene coding for 5-HTT (i.e., resulting in increased 5-HT signaling) resulted in reduced 5-HT4 density. From studies in humans we also know that acute blockade of 5-HTT with citalopram, putatively resulting in increased 5-HT signaling, did not modify [11C]SB207145 binding (Marner et al., 2010). Taken together, these findings suggest that [11C]SB207145 PET may be a useful proxy for chronically, but not acutely, altered cerebral 5-HT levels. Thus, evaluating the impact of 5-HTTLPR status on [11C]SB207145 binding would benefit our understanding of how this polymorphism may bias cerebral 5-HT neurotransmission in humans, in vivo.
In the current study, we sought to determine whether 5-HTTLPR status predicted [11C]SB207145 binding in 47 healthy adult volunteers. Based on the anticipated effects of the 5-HTTLPR on synaptic 5-HT signaling and the monotonic association between 5-HT4 levels and 5-HT signaling, we hypothesized that S carriers would exhibit reduced [11C]SB207145 binding relative to L/L individuals. Additionally, we evaluated whether seasonal fluctuation or daylight minutes moderated the effect of 5-HTTLPR status on [11C]SB207145 binding, hypothesizing that the S allele would be associated with greater season-associated fluctuations in [11C]SB207145 binding reflecting a diminished capacity for regulating 5-HT signaling in response to an environmental stressor (Kalbitzer et al., 2010).
Section snippets
Participants
Forty-seven healthy participants (35 males; age: mean ± s.d. = 34.9 ± 17.7, median = 26.9, range = 20–86) were recruited by advertisement for a research protocol approved by the Ethics Committee of Copenhagen and Frederiksberg, Denmark [KF-01-274821, KF-11-282837, H-KF-274821]. After complete description of the study to the participants, written informed consent was obtained from all participants. Exclusion criteria for all participants included 1) primary psychiatric disease, 2) substance or drug abuse
[11C]207145 binding and demographic variables
A summary of demographic variables and PET parameters can be found in Table 1. Genotype groups based on observed allele frequency were in Hardy–Weinberg equilibrium (X2 = 0.09, p = 0.77). Differences between genotype groups for demographic variables and PET parameters can be found in Table 1. Age was significantly different between 5-HTTLPR genotype groups such that LL individuals were older than S carriers (p = 0.007). Additionally, we observed differences in BMI and weight-adjusted injected mass
Discussion
We used an imaging genetics approach to evaluate the association between 5-HTTLPR status and [11C]SB207145 binding, assessed using in vivo PET, within a population of healthy adults with no history of psychopathology. Consistent with our hypothesis, we identified an association between 5-HTTLPR status and [11C]SB207145 binding such that S carriers exhibited reduced binding relative to L/L homozygotes. Specifically, we observed this effect within the neocortex and a trend for a similar effect
Conclusions
In summary, we find evidence for an association between 5-HTTLPR status and 5-HT4 binding, assessed with [11C]SB207145 PET, such that S carriers display reduced neocortical binding relative to LL homozygotes. We do not observe evidence for an effect of season on [11C]SB207145 binding, which may reflect regulation of 5-HT signaling in response to seasonal variation via alternative mechanisms (e.g., regulation of 5-HTT levels). Considering animal studies that indicate the 5-HT4 receptor shows a
Financial disclosures
The authors declare no conflict of interest.
Acknowledgments
We would like to thank G. Thomsen, S. Larsen, A. Dyssegaard, L. Bech, K. Christiansen and L. Freyr for their assistance in scheduling and data collection at both the MR and PET centers. We would like to gratefully acknowledge The John and Birthe Meyer Foundation for the donation of the Cyclotron and PET-scanner. This study was funded by a center grant to Cimbi from the Lundbeck Foundation. Data presented here were also presented by Dr. Fisher as a poster at the 2011 European Congress of
References (45)
- et al.
Possible serotonergic mechanisms underlying the antidepressant and anti-obsessive–compulsive disorder responses
Biol. Psychiatry
(1998) - et al.
The personality trait openness is related to cerebral 5-HTT levels
Neuroimage
(2009) - et al.
Seasonal changes in brain serotonin transporter binding in short serotonin transporter linked polymorphic region-allele carriers but not in long-allele homozygotes
Biol. Psychiatry
(2010) - et al.
Effects of the 5-HT4 receptor agonist RS67333 and paroxetine on hippocampal extracellular 5-HT levels
Neurosci. Lett.
(2010) The spectrum of behaviors influenced by serotonin
Biol. Psychiatry
(1998)- et al.
Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET
Neuroimage
(2010) - et al.
Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis
Biol. Psychiatry
(2008) - et al.
Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain
Neuroimage
(2010) - et al.
Altered serotonin 1A binding in major depression: A [carbonyl-C-11]WAY100635 positron emission tomography study
Biol. Psychiatry
(2006) - et al.
Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study
Biol. Psychiatry
(2007)
MR-based automatic delineation of volumes of interest in human brain PET images using probability maps
Neuroimage
Imaging the effects of genetic polymorphisms on radioligand binding in the living human brain: a review on genetic neuroreceptor imaging of monoaminergic systems in psychiatry
Neuroimage
The primate serotonergic system: a review of human and animal studies and a report on Macaca fascicularis
Adv. Neurol.
Serotonin transporter genotype is associated with cognitive performance but not regional 5-HT1A receptor binding in humans
Int. J. Neuropsychopharmacol.
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Science
Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits
Am. J. Psychiatry
Cell-specific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism
J. Neurosci.
A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans
J. Neurosci.
Effects of HTR1A C(− 1019)G on amygdala reactivity and trait anxiety
Arch. Gen. Psychiatry
Capacity for 5-HT1A‐mediated autoregulation predicts amygdala reactivity
Nat. Neurosci.
Identification of neurogenetic pathways of risk for psychopathology
Am. J. Med. Genet. C Semin. Med. Genet.
Medial prefrontal cortex 5-HT2A density is correlated with amygdala reactivity, response habituation, and functional coupling
Cereb. Cortex
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