Genetic variation in 5-hydroxytryptamine transporter expression causes adaptive changes in 5-HT4 receptor levels

Jennings, Katie A.; Licht, Cecilie Löe; Bruce, A White; Lesch, Klaus‐Peter; Knudsen, Gitte M.; Sharp, Trevor

doi:10.1017/s1461145711001258

Cited by 22 publications

(23 citation statements)

References 45 publications

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“…Specifically, we observed this effect within the neocortex and a trend for a similar effect within the caudate whereas we did not observe evidence for an effect of 5-HTTLPR status on [ 11 C]SB207145 binding within subcortical regions including the amygdala, hippocampus and putamen. Previous studies in animal models have reported that 5-HT 4 levels show a monotonic response to chronic changes in 5-HT levels (Jennings et al, 2011;Licht et al, 2010;Vidal et al, 2009). Based on these animal studies, our current findings suggest that 5-HTTLPR status may contribute to differences in cerebral 5-HT levels that are identifiable in humans using in vivo neuroimaging.…”

Section: Discussionmentioning

confidence: 95%

“…A recent study in mice reported that homozygous knock-out of the gene coding for the 5-HTT resulted in a down-regulation of 5-HT 4 binding measured with [ 3 H]SB207145 (Jennings et al, 2011). Conversely, over-expression of the gene coding for the 5-HTT resulted in increased 5-HT 4 binding.…”

Section: Discussionmentioning

confidence: 99%

“…Recent animal studies have reported that cerebral 5-HT 4 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-HT 4 density in mice (Jennings et al, 2011). Specifically, mice overexpressing 5-HTT (i.e., resulting in reduced 5-HT signaling) showed increased 5-HT 4 density while knock-out of the gene coding for 5-HTT (i.e., resulting in increased 5-HT signaling) resulted in reduced 5-HT 4 density.…”

Section: Introductionmentioning

confidence: 99%

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5-HTTLPR status predictive of neocortical 5-HT4 binding assessed with [11C]SB207145 PET in humans

et al. 2012

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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5-HTTLPR status predictive of neocortical 5-HT4 binding assessed with [11C]SB207145 PET in humans

et al. 2012

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“…However, we cannot rule out adaptive changes in the serotoninergic system, including variations in 5-HT 4 receptor levels, which could explain the absence of behavioral effects of fluoxetine in 5-HT 1A receptor KO mice. Indeed, decreases in the density of the serotonin transporter (5-HTT) were measured in several brain regions of these 5-HT 1A mutant mice (Ase et al, 2001), and a recent study described that variation in serotonin transporter expression could cause adaptive changes in 5-HT 4 receptor levels in serotonin transporter overexpressing mice (Jennings et al, 2012).…”

Section: Requirement Of 5-ht 4 Receptors For the Behavioral And Neuromentioning

confidence: 99%

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

Mendez‐David

David

Darcet

et al. 2013

Neuropsychopharmacol

142

152

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Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work in naive rats showed that 5-HT 4 receptor agonists had rapid effects on depression-related behaviors and on hippocampal neurogenesis. We decided to investigate whether 5-HT 4 receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression, and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT 4 receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety-and depression-related behaviors, as well as on hippocampal neurogenesis in comparison with chronic fluoxetine treatment (18 mg/kg/day). Then, using our anxiety/depression model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7 days) or chronic (28 days) RS67333 treatment. We also assessed whether a 5-HT 4 receptor antagonist (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis, specifically facilitating maturation of newborn neurons. However, unlike fluoxetine, anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT 4 receptor activation is necessary for these effects of SSRIs. 5-HT 4 receptor stimulation could represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.

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“…SERT knockout rats exhibit highly parallel findings to those found in SERT knockout mice. Transgenic SERT over-expressing mice show reduced anxiety and related behaviors and other reversed phenomena including serotonin receptor changes compared to SERT-deficient mice (reviews: [41, 55]).…”

Section: Introductionmentioning

confidence: 99%

The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction

Rudnick

Krämer

Blakely

et al. 2013

Pflugers Arch - Eur J Physiol

139

130

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The human SLC6 family is composed of approximately 20 structurally related symporters (co-transporters) that use the transmembrane electrochemical gradient to actively import their substrates into cells. Approximately half of the substrates of these transporters are amino acids, with others transporting biogenic amines and/or closely related compounds, such as nutrients and compatible osmolytes. In this short review, five leaders in the field discuss a number of currently important research themes that involve SLC6 transporters, highlighting the integrative role they play across a wide spectrum of different functions. The first essay, by Gary Rudnick, describes the molecular mechanism of their coupled transport which is being progressively better understood based on new crystal structures, functional studies, and modeling. Next, the question of multiple levels of transporter regulation is discussed by Reinhard Krämer, in the context of osmoregulation and stress response by the related bacterial betaine transporter BetP. The role of selected members of the human SLC6 family that function as nutrient amino acid transporters is then reviewed by François Verrey. He discusses how some of these transporters mediate the active uptake of (essential) amino acids into epithelial cells of the gut and the kidney tubule to support systemic amino acid requirements, whereas others are expressed in specific cells to support their specialized metabolism and/or growth. The most extensively studied members of the human SLC6 family are neurotransmitter reuptake transporters, many of which are important drug targets for the treatment of neuropsychiatric disorders. Randy Blakely discusses the role of posttranscriptional modifications of these proteins in regulating transporter subcellular localization and activity state. Finally, Dennis Murphy reviews how natural gene variants and mouse genetic models display consistent behavioral alterations that relate to altered extracellular neurotransmitter levels.

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Genetic variation in 5-hydroxytryptamine transporter expression causes adaptive changes in 5-HT4 receptor levels

Cited by 22 publications

References 45 publications

5-HTTLPR status predictive of neocortical 5-HT4 binding assessed with [11C]SB207145 PET in humans

5-HTTLPR status predictive of neocortical 5-HT4 binding assessed with [11C]SB207145 PET in humans

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction

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