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

Murthy, Naga Venkatesha; Selvaraj, Sudhakar; Cowen, Philip J.; Bhagwagar, Zubin; Riedel, Wim J.; Peers, Polly V.; Kennedy, James L.; Sahakian, Barbara J.; Laruelle, Marc; Rabiner, Eugenii A.; Grasby, Paul M.

doi:10.1016/j.neuroimage.2010.04.032

Cited by 83 publications

(56 citation statements)

References 25 publications

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“…17,19 By contrast, positron emission tomography (PET) studies in humans, investigating the SERT in vivo, provided evidence that expression of the transporter remained unaffected by this allele. 29 Third, although the risk for psychopathology in the presence of low 5-HT is less inevitable according to the low 5-HT diathesis-stress model than the 5-HT deficit model, the 5-HT diathesis-stress model is still somewhat deterministic. For instance, the model does not take into account resilience, nor does it account for non-stress induced relapses, a clinical phenomenon very common in, for example, depressed patients with a history of multiple episodes.…”

Section: J Psychiatry Neurosci 2015;40(1)mentioning

confidence: 99%

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

Booij

Tremblay

Szyf

et al. 2015

jpn

108

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Section: J Psychiatry Neurosci 2015;40(1)mentioning

confidence: 99%

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

Booij

Tremblay

Szyf

et al. 2015

jpn

108

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“…Although the influence of the 5-HTTLPR on promoter activity and the production of mRNA, protein product, and 5-HT reuptake activity has been documented in cellular assays (Bradley et al, 2005;Heils et al, 1996;Lesch et al, 1996;Philibert et al, 2008;Stoltenberg et al, 2002), paradoxically nearly all attempts to examine the influence of 5-HTTLPR promoter variants on 5-HTT levels in adult brain have been negative (Lim et al, 2006;Murthy et al, 2010;Oquendo et al, 2007;Parsey et al, 2006;Preuss et al, 2000). This disconnect leaves open the possibility of a more prominent impact of the 5-HTTLPR on developmental 5-HTT expression, including transient 5-HTT expression during human fetal development.…”

Section: Clinical Relevancementioning

confidence: 99%

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

Suri

Teixeira

Cagliostro

et al. 2014

Neuropsychopharmacol

145

125

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Development passes through sensitive periods, during which plasticity allows for genetic and environmental factors to exert indelible influence on the maturation of the organism. In the context of central nervous system development, such sensitive periods shape the formation of neurocircuits that mediate, regulate, and control behavior. This general mechanism allows for development to be guided by both the genetic blueprint as well as the environmental context. While allowing for adaptation, such sensitive periods are also vulnerability windows during which external and internal factors can confer risk to disorders by derailing otherwise resilient developmental programs. Here we review developmental periods that are sensitive to monoamine signaling and impact adult behaviors of relevance to psychiatry. Specifically, we review (1) a serotonin-sensitive period that impacts sensory system development, (2) a serotonin-sensitive period that impacts cognition, anxiety-and depressionrelated behaviors, and (3) a dopamine-and serotonin-sensitive period affecting aggression, impulsivity and behavioral response to psychostimulants. We discuss preclinical data to provide mechanistic insight, as well as epidemiological and clinical data to point out translational relevance. The field of translational developmental neuroscience has progressed exponentially providing solid conceptual advances and unprecedented mechanistic insight. With such knowledge at hand and important methodological innovation ongoing, the field is poised for breakthroughs elucidating the developmental origins of neuropsychiatric disorders, and thus understanding pathophysiology. Such knowledge of sensitive periods that determine the developmental trajectory of complex behaviors is a necessary step towards improving prevention and treatment approaches for neuropsychiatric disorders.

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“…This tracer has previously been used in pharmaceutical and clinical human PET studies as a high-affinity and highly selective radioligand for SERT (4,5).…”

mentioning

confidence: 99%

In Vivo Evaluation of ¹¹C-DASB for Quantitative SERT Imaging in Rats and Mice

et al. 2015

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Serotonin, or 5-hydroxytryptamine (5-HT), plays a key role in the central nervous system and is involved in many essential neurologic processes such as mood, social behavior, and sleep. The serotonin transporter ligand 11 C-3-amino-4(2-dimethylaminomethyl-phenylsufanyl)-benzonitrile ( 11 C-DASB) has been used to determine nondisplaceable binding potential (BP ND ), which is defined as the quotient of the available receptor density (B avail ) and the apparent equilibrium dissociation rate constant (1/appK D ) under in vivo conditions. Because of the increasing number of animal models of human diseases, there is a pressing need to evaluate the applicability of 11 C-DASB to rats and mice. Here, we assessed the feasibility of using 11 C-DASB for quantification of serotonin transporter (SERT) density and affinity in vivo in rats and mice. Methods: Rats and mice underwent 4 PET scans with increasing doses of the unlabeled ligand to calculate B avail and appK D using the multiple-ligand concentration transporter assay. An additional PET scan was performed to calculate test-retest reproducibility and reliability. BP ND was calculated using the simplified reference tissue model, and the results for different reference regions were compared. Results: Displaceable binding of 11 C-DASB was found in all brain regions of both rats and mice, with the highest binding being in the thalamus and the lowest in the cerebellum. In rats, displaceable binding was largely reduced in the cerebellar cortex, which in mice was spatially indistinguishable from cerebellar white matter. Use of the cerebellum with fully saturated binding sites as the reference region did not lead to reliable results. Test-retest reproducibility in the thalamus was more than 90% in both mice and rats. In rats, B avail , appK D , and ED 50 were 3.9 ± 0.4 pmol/mL, 2.2 ± 0.4 nM, and 12.0 ± 2.6 nmol/kg, respectively, whereas analysis of the mouse measurements resulted in inaccurate fits due to the high injected tracer mass. Conclusion: Our data showed that in rats, 11 C-DASB can be used to quantify SERT density with good reproducibility. BP ND agreed with the distribution of SERT in the rat brain. It remains difficult to estimate quantitative parameters accurately from mouse measurements because of the high injected tracer mass and underestimation of the binding parameters due to high displaceable binding in the reference region. Ser otonergic neurons accumulate mainly in the brainstem and form the raphe nuclei (1). Although the raphe nuclei consist of only a few neurons, these nuclei innervate nearly all brain regions (1). Under normal physiologic conditions, the membranebound, sodium-chloride-dependent SERT (serotonin transporter, or 5-hydroxytryptamine [5-HT] transporter) is responsible for specific reuptake of released serotonin by cells (2). This transporter is located on the soma, dendritic collaterals, and entire axon of serotonergic neurons (3).One of the most promising noninvasive imaging approaches for visualizing the distribution of SERT is the SERT mark...

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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

Cited by 83 publications

References 25 publications

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

In Vivo Evaluation of ¹¹C-DASB for Quantitative SERT Imaging in Rats and Mice

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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

Cited by 83 publications

References 25 publications

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

In Vivo Evaluation of 11C-DASB for Quantitative SERT Imaging in Rats and Mice

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Product

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In Vivo Evaluation of ¹¹C-DASB for Quantitative SERT Imaging in Rats and Mice