5-HT4R Binding Research Articles

Effect of Antidepressant Treatment on 5-HT4 Receptor Binding and Associations With Clinical Outcomes and Verbal Memory in Major Depressive Disorder

BackgroundBrain serotonin 4 receptor (5-HT4R) levels are lower in untreated patients with major depressive disorder (MDD) and are linked to verbal memory. Here, we investigated the relationship between 5-HT4R levels, clinical outcomes, and cognitive function in patients with MDD who initiated selective serotonin reuptake inhibitor drug treatment. MethodsNinety patients with moderate to severe depression underwent molecular brain imaging to measure 5-HT4R binding prior to antidepressant treatment with escitalopram. Pretreatment 5-HT4R binding was assessed for its ability to predict treatment outcome at weeks 4, 8, or 12. In 40 patients who were rescanned 8 weeks posttreatment, change in cerebral 5-HT4R binding was correlated with change in verbal memory and with change in depressive symptoms, as evaluated by the 6-item Hamilton Depression Rating Scale. ResultsAfter 8 weeks of serotonergic intervention, neostriatal 5-HT4R binding was reduced by 9%. Global change in 5-HT4R binding from baseline was associated with verbal memory outcomes, but not with overall clinical depressive symptom outcomes. Pretreatment 5-HT4R binding did not predict clinical recovery status at week 8 and was not associated with change in the 6-item Hamilton Depression Rating Scale scores. ConclusionsIn patients with moderate to severe MDD, treatment with selective serotonin reuptake inhibitors downregulated neostriatal 5-HT4R levels, which is consistent with the notion that the drugs increase cerebral extracellular serotonin. The less global brain 5-HT4R levels were downregulated after selective serotonin reuptake inhibitors, the more verbal memory improved, highlighting the potential importance of 5-HT4R as a treatment target in MDD. The findings offer insights into mechanisms that underlie antidepressant effects and point to new directions for precision medicine treatments for MDD.

Low-grade inflammation and serotonin 4 receptor binding in the healthy and the depressed brain

Inflammatory status affects healthy brain function and also low-grade inflammation putatively contributes to the pathophysiology of Major Depressive Disorder (MDD). This psychoneuro-immunological interplay is complex, bidirectional, and not fully understood. Also, it is not clear to what extent depressive states induce inflammation and/or if increased inflammation leads to depressive symptoms by affecting brain biology including serotonin signaling. The serotonin 4 receptor (5-HT4R) is an interesting new antidepressant target; direct stimulation has antidepressant-like, and pro-cognitive effects, and may also index serotonin tone at least in the adult healthy brain.Here, we investigate whether a peripheral marker of low-grade inflammation (hsCRP) is associated with 5-HT4R brain binding in both a healthy and in an unmedicated MDD group. 5-HT4R PET imaging data and hsCRP measures from 112 healthy and 79 unmedicated MDD individuals were available from the Cimbi database. We evaluated the associations between hsCRP level and 5-HT4R binding in three regions of interest (neocortex, hippocampus, and neostriatum) using multiple linear regression models adjusted for relevant covariates.We did not observe a statistically significant association between hsCRP and 5-HT4R binding. This applied to both the healthy and the MDD group.Our findings do not support a coupling between low-grade inflammation and brain 5-HT4R availability, which suggests that the serotonergic system is not sensitive to low-grade inflammation captured by hsCRP, neither in healthy nor in depressed states. Future studies are needed to test if the brain serotonin system is coupled to other inflammatory markers, for instance in conditions with high-grade and/or prolonged immunoactivation.

Serotonin 4 receptor brain binding and oxytocin-promoted affective and social cognition in healthy women – A randomized controlled trial

BackgroundOxytocin is a neuropeptide known for its prosocial properties and role in social bonding, and intervention with intranasal oxytocin is posited to modulate affective and social cognition (i.e., hot cognition). Serotonin (5-HT) neurotransmission is also involved in emotional and social behaviors and appear to work in concert with oxytocin. However, this interaction so far remains elusive in humans. Therefore, we here investigate the relation between brain 5-HT 4 receptor (5-HT4R) levels and oxytocin-modulated hot cognition. MethodsUsing a double blind, placebo-controlled, randomized crossover design, 35 healthy women received a dose of 24 IU intranasal oxytocin or placebo one month apart. The women were naturally cycling and to control for hormonal fluctuations across the menstrual cycle, intervention days were placed during the early follicular phase. Following intervention cognitive domains including affective memory, affective bias in emotion processing, moral emotions and social information preference were assessed. In a subgroup (n = 25), Positron Emission Tomography (PET) was used to image 5-HT4R brain binding at baseline with the [11C]SB207145 radiotracer. ResultsNo effect of oxytocin intervention relative to placebo was observed for any of the cognitive outcomes. Likewise, regional brain 5-HT4R binding at baseline was not associated with cognitive responses to oxytocin intervention. ConclusionOur data suggest that intervention with intranasal oxytocin does not have an overall effect on hot cognition in healthy women and further that 5-HT4R brain architecture does not mediate cognitive effects of oxytocin in the healthy state.

No association between serotonin 4 receptor brain binding and personality trait Neuroticism - A positron emission tomography study in depressed patients and healthy individuals

Serotonergic neurotransmission has been linked to normal personality functioning, including the five-factor personality trait Neuroticism, which is a robust risk factor for Major Depressive Disorder (MDD). The serotonin 4 receptor (5-HT4R) is involved in regulating mood and has been shown to be altered in patients with MDD and map onto anxiety levels and memory performance. We here evaluate the link between 5-HT4R levels and Neuroticism in patients with MDD and replicate a previous study in healthy individuals. Neuroticism scores and brain 5-HT4R binding potential assessed with [11C]SB207145 positron emission tomography (PET) imaging were available from the CIMBI database for 63 unmedicated patients with MDD (48 W) and 120 healthy individuals (67 W). We investigated the association between Neuroticism and 5-HT4R binding in six regions of interest: frontal cortex, anterior cingulate cortex, amygdala, hippocampus, neostriatum, and thalamus for each group. There was no association between regional 5-HT4R binding and total Neuroticism score in patients or healthy individuals (all padj > 0.99), although post hoc analyses indicated that in patients, Neuroticism facets of Depression (padj = 0.046) and Impulsivity (padj = 0.009) were positively associated with thalamic and frontal 5-HT4R binding respectively. While trait Neuroticism does not appear to be associated with brain 5-HT4R in either patients with MDD or healthy individuals, we found evidence that the facets Depression and Impulsiveness may be linked to regional 5-HT4R levels in patients.

Stress Hormone Dynamics Are Coupled to Brain Serotonin 4 Receptor Availability in Unmedicated Patients With Major Depressive Disorder: A NeuroPharm Study.

A prominent finding in major depressive disorder (MDD) is distorted stress hormone dynamics, which is regulated by serotonergic brain signaling. An interesting feature of the cerebral serotonin system is the serotonin 4 receptor (5-HT4R), which is lower in depressed relative to healthy individuals and also has been highlighted as a promising novel antidepressant target. Here, we test the novel hypothesis that brain 5-HT4R availability in untreated patients with MDD is correlated with cortisol dynamics, indexed by the cortisol awakening response (CAR). Further, we evaluate if CAR changes with antidepressant treatment, including a selective serotonin reuptake inhibitor, and if pretreatment CAR can predict treatment outcome. Sixty-six patients (76% women) with a moderate to severe depressive episode underwent positron emission tomography imaging with [11C]SB207145 for quantification of brain 5-HT4R binding using BPND as outcome. Serial home sampling of saliva in the first hour from awakening was performed to assess CAR before and after 8 weeks of antidepressant treatment. Treatment outcome was measured by change in Hamilton Depression Rating Scale 6 items. In the unmedicated depressed state, prefrontal and anterior cingulate cortices 5-HT4R binding was positively associated with CAR. CAR remained unaltered after 8 weeks of antidepressant treatment, and pretreatment CAR did not significantly predict treatment outcome. Our findings highlight a link between serotonergic disturbances in MDD and cortisol dynamics, which likely is involved in disease and treatment mechanisms. Further, our data support 5-HT4R agonism as a promising precision target in patients with MDD and disturbed stress hormone dynamics.

Sexual health and serotonin 4 receptor brain binding in unmedicated patients with depression—a NeuroPharm study

Sexual dysfunction is prominent in Major Depressive Disorder (MDD) and affects women with depression more than men. Patients with MDD relative to healthy controls have lower brain levels of the serotonin 4 receptor (5-HT4R), which is expressed with high density in the striatum, i.e. a key hub of the reward system. Reduced sexual desire is putatively related to disturbed reward processing and may index anhedonia in MDD. Here, we aim to illuminate plausible underlying neurobiology of sexual dysfunction in unmedicated patients with MDD. We map associations between 5-HT4R binding, as imaged with [11C]SB207145 PET, in the striatum, and self-reported sexual function. We also evaluate if pre-treatment sexual desire score predicts 8-week treatment outcome in women. From the NeuroPharm study, we include 85 untreated MDD patients (71% women) who underwent eight weeks of antidepressant drug treatment. In the mixed sex group, we find no difference in 5-HT4R binding between patients with sexual dysfunction vs normal sexual function. However, in women we find lower 5-HT4R binding in the sexual dysfunctional group compared to women with normal sexual function (β = −0.36, 95%CI[−0.62:−0.09], p = 0.009) as well as a positive association between sexual desire and 5-HT4R binding (β = 0.07, 95%CI [0.02:0.13], p = 0.012). Sexual desire at baseline do not predict treatment outcome (ROC curve AUC = 52%[36%:67%]) in women. Taken together, we find evidence for a positive association between sexual desire and striatal 5-HT4R availability in women with depression. Interestingly, this raises the question if direct 5-HT4R agonism can target reduced sexual desire or anhedonia in MDD.

Association between brain serotonin 4 receptor binding and reactivity to emotional faces in depressed and healthy individuals

Brain serotonergic (5-HT) signaling is posited to modulate neural responses to emotional stimuli. Dysfunction in 5-HT signaling is implicated in major depressive disorder (MDD), a disorder associated with significant disturbances in emotion processing. In MDD, recent evidence points to altered 5-HT4 receptor (5-HT4R) levels, a promising target for antidepressant treatment. However, how these alterations influence neural processing of emotions in MDD remains poorly understood. This is the first study to examine the association between 5-HT4R binding and neural responses to emotions in patients with MDD and healthy controls. The study included one hundred and thirty-eight participants, comprising 88 outpatients with MDD from the NeuroPharm clinical trial (ClinicalTrials.gov identifier: NCT02869035) and 50 healthy controls. Participants underwent an [11C]SB207145 positron emission tomography (PET) scan to quantify 5-HT4R binding (BPND) and a functional magnetic resonance imaging (fMRI) scan during which they performed an emotional face matching task. We examined the association between regional 5-HT4R binding and corticolimbic responses to emotional faces using a linear latent variable model, including whether this association was moderated by depression status. We observed a positive correlation between 5-HT4R BPND and the corticolimbic response to emotional faces across participants (r = 0.20, p = 0.03). This association did not differ between groups (parameter estimate difference = 0.002, 95% CI = −0.008: 0.013, p = 0.72). Thus, in the largest PET/fMRI study of associations between serotonergic signaling and brain function, we found a positive association between 5-HT4R binding and neural responses to emotions that appear unaltered in MDD. Future clinical trials with novel pharmacological agents targeting 5-HT4R are needed to confirm whether they ameliorate emotion processing biases in MDD.

Association between the loudness dependence of auditory evoked potential, serotonergic neurotransmission and treatment outcome in patients with depression

Previous studies have suggested that the loudness dependence of auditory evoked potential (LDAEP) is associated with the effectiveness of antidepressant treatment in patients with major depressive disorders (MDD). Furthermore, both LDAEP and the cerebral serotonin 4 receptor (5-HT4R) density is inversely related to brain serotonin levels.We included 84 patients with MDD and 22 healthy controls to examined the association between LDAEP and treatment response and its association with cerebral 5-HT4R density. Participants underwent both EEG and 5-HT4R neuroimaging with [11C]SB207145 PET. Thirty-nine patients with MDD were re-examined after 8 weeks of treatment with selective serotonin reuptake inhibitors/serotonin noradrenaline reuptake inhibitor (SSRI/SNRI).We found that the cortical source of LDAEP was higher in untreated patients with MDD compared to healthy controls (p=0.03). Prior to SSRI/SNRI treatment, subsequent treatment responders had a negative association between LDAEP and depressive symptoms and a positive association between scalp LDAEP and symptom improvement at week 8. This was not found in source LDAEP. In healthy controls, we found a positive correlation between both scalp and source LDAEP and cerebral 5-HT4R binding but that was not observed in patients with MDD. We did not see any changes in scalp and source LDAEP in response to SSRI/SNRI treatment.These results support a theoretical framework where both LDAEP and cerebral 5-HT4R are indices of cerebral 5-HT levels in healthy individuals while this association seems to be disrupted in MDD. The combination of the two biomarkers may be useful for stratifying patients with MDD.Clinical Trials Registration:https://clinicaltrials.gov/ct2/show/NCT02869035?draw=1Registration number: NCT0286903.

Concurrent anxiety in patients with major depression and cerebral serotonin 4 receptor binding. A NeuroPharm-1 study

Concurrent anxiety is frequent in major depressive disorder and a shared pathophysiological mechanism between anxiety and other depressive symptoms is plausible. The serotonin 4 receptor (5-HT4R) has been implicated in both depression and anxiety. This is the first study to investigate the association between the cerebral 5-HT4R binding and anxiety in patients with depression before and after antidepressant treatment and the association to treatment response. Ninety-one drug-free patients with depression were positron emission tomography scanned with the 5-HT4R ligand [11C]-SB207145. Depression severity and concurrent anxiety was measured at baseline and throughout 8 weeks of antidepressant treatment. Anxiety measures included four domains: anxiety/somatization factor score; Generalized Anxiety Disorder 10-items (GAD-10) score; anxiety/somatization factor score ≥7 (anxious depression) and syndromal anxious depression. Forty patients were rescanned at week 8. At baseline, we found a negative association between global 5-HT4R binding and both GAD-10 score (p < 0.01) and anxiety/somatization factor score (p = 0.06). Further, remitters had a higher baseline anxiety/somatization factor score compared with non-responders (p = 0.04). At rescan, patients with syndromal anxious depression had a greater change in binding relative to patients with non-syndromal depression (p = 0.04). Concurrent anxiety in patients with depression measured by GAD-10 score and anxiety/somatization factor score is negatively associated with cerebral 5-HT4R binding. A lower binding may represent a subtype with reduced natural resilience against anxiety in a depressed state, and concurrent anxiety may influence the effect on the 5-HT4R from serotonergic antidepressants. The 5-HT4R is a promising neuroreceptor for further understanding the underpinnings of concurrent anxiety in patients with depression.

Evidence for a Serotonergic Subtype of Major Depressive Disorder

Background: First line pharmacological treatment of Major Depressive Disorder (MDD) is selective serotonin reuptake inhibitors (SSRIs), but only 1/3 of patients obtain remission. Cerebral serotonin 4 receptor (5-HT4R) binding measured with positron emission tomography (PET) is inversely related to serotonin levels and can serve as a proxy for brain serotonin levels. We here determine if a successful outcome of serotonergic treatment in MDD is linked to a serotonergic deficit. Methods: We [11C]-SB207145 PET-scanned 100 untreated patients with moderate to severe MDD and 91 healthy controls; 40 patients were re-scanned after 8 weeks treatment. All patients were started on SSRI and were followed up clinically after 1, 2, 4, 8 and 12 weeks. Treatment response was measured as change from baseline in Hamilton depression rating scale 6 score. Findings: Before treatment, patients with MDD had 8% lower global 5-HT4R binding than controls (95% confidence interval [-13·1%;-2·5%], p<0·001). Non-responders did not differ from controls ([-11·5%;4·0%], p=0.31), whereas remitters had 9% lower binding than controls at baseline ([-16·1%;-2·7%], p=0.004). The probability that a remitter had a lower baseline 5-HT4R neocortex binding compared to a non-responder was 0.63 [0.43;0.84] with p=0.20.Independent of treatment outcomes, patients reduced their neostriatal 5-HT4R binding (-9%, [-12·8%;-5·0%], p<0·001, N=40) after serotonergic intervention. Interpretation: Patients with MDD who remit to SSRIs have lower cerebral 5-HT4R levels than controls whereas non-responders do not differ, suggesting the presence of a serotonergic subtype of MDD. While SSRI intervention decreased neostriatal 5-HT4R, the change was not associated with the individual clinical outcome. Our data suggest that non-responders to SSRI’s constitute a subgroup with non-serotonergic depression. Trial Registration: Registered as a clinical trial before initiation (NCT02869035). Funding Statement: Key economic support was granted from the Innovation Fund Denmark, Research Fund of the Mental Health Services - Capital Region of Denmark, Independent Research Fund Denmark, G.J. Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savvaerksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation and the H. Lundbeck A/S. H. Declaration of Interests: GMK has received honoraria as expert advisor for Sage Therapeutics and as speaker for Jannsen. VGF has served as consultant for SAGE therapeutics. MBJ has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other authors declare no conflict of interest. Ethics Approval Statement: The study protocol was approved by all relevant authorities (the Health Research Ethics Committee of the Capital Region of Denmark (H15017713), the Danish Data Protection Agency (04711/RH-2016-163) and Danish Medicines Agency (EudraCT- 2016-001626-34)). All participants provided written informed consent prior to inclusion.

P.553 5-HT4R binding is positively correlated with obsessive-compulsive features: a preliminary analysis in healthy volunteers

The aim of the present study was to investigate the differences in the topological organization of functional brain networks between children with growth hormone deficiency (GHD) and those with idiopathic short stature (ISS).Thirty-one children with GHD and fifty-three children with ISS were recruited based on the results of GH stimulation tests. Resting-state fMRI data were acquired from all children. Whole brain functional connectivity density (FCD) analysis and subsequent seed-based functional connectivity analysis were used to explore the differences in functional brain networks between the children with ISS and GHD. Correlation analyses among the results of clinical laboratory examinations, neuropsychological scales and FCD values of different brain regions were applied.Compared with the ISS group, the GHD group exhibited significantly decreased FCDs in the left postcentral gyrus, right precentral gyrus and left cerebellar lobules 7b and 6. The subsequent functional connectivity analysis found decreased functional connectivity between lobules 7b and 6 of the left cerebellum as well as the left postcentral gyrus and right precentral gyrus in the GHD group compared to that in the ISS group. In addition, the FCD values of region 6 of the left cerebellum in the GHD group were negatively correlated with the scores on the Symptom Checklist-90 and Eysenck Personality Questionnaire. The FCD value of the left postcentral gyrus in children with ISS positively correlated with IGFBP-3 levels and was approximately correlated with IGF-1 levels.These findings highlight the impact of growth hormone deficiency on the brain network that mainly involves the somatosensory, somatic motor and cerebellum networks, which may contribute to the behavioural problems observed in these children.

Seasonality-resilient individuals downregulate their cerebral 5-HT transporter binding in winter – A longitudinal combined 11C-DASB and 11C-SB207145 PET study

We have recently shown that the emergence and severity of seasonal affective disorder (SAD) symptoms in the winter is associated with an increase in cerebral serotonin (5-HT) transporter (SERT) binding. Intriguingly, we also found that individuals resilient to SAD downregulate their cerebral SERT binding in the winter. In the present paper, we provide an analysis of the SERT- and 5-HT dynamics as indexed by 5-HT4 receptor (5-HT4R) binding related to successful stress coping. We included 46 11C-DASB positron emission tomography (PET) scans (N = 23, 13 women, age: 26 ± 6 years) and 14 11C-SB207145 PET scans (7 participants, 3 women, age: 25 ± 3 years) from 23 SAD-resilient Danes. Data was collected longitudinally in summer and winter. We found that compared to the summer, raphe nuclei and global brain SERT binding decreased significantly in the winter (praphe = 0.003 and pglobal = 0.003) and the two measures were positively correlated across seasons (summer: R2 = 0.33, p = .004, winter: R2 = 0.24, p = .018). A voxel-based analysis revealed prominent changes in SERT in clusters covering both angular gyri (0.0005 < pcorrected < 0.0016), prefrontal cortices (0.00087 < pcorrected < 0.0039) and the posterior temporal and adjacent occipital cortices (0.0001 < pcorrected < 0.0066). We did not observe changes in 5-HT4R binding, suggesting that 5-HT levels remained stable across seasons. We conclude that resilience to SAD is associated with a global downregulation of SERT levels in winter which serves to keep 5-HT levels across seasons.

No evidence for a role of the serotonin 4 receptor in five-factor personality traits: A positron emission tomography brain study.

Serotonin (5-HT) brain architecture appears to be implicated in normal personality traits as supported by genetic associations and studies using molecular brain imaging. However, so far, no studies have addressed potential contributions to variation in normal personality traits from in vivo serotonin 4 receptor (5-HT4R) brain availability, which has recently become possible to image with Positron Emission Tomography (PET). This is particularly relevant since availability of 5-HT4R has been shown to adapt to synaptic levels of 5-HT and thus offers information about serotonergic tone in the healthy brain. In 69 healthy participants (18 females), the associations between personality traits assessed with the five-factor NEO Personality Inventory-Revised (NEO PI-R) and regional cerebral 5-HT4R binding in neocortex, amygdala, hippocampus, and anterior cingulate cortex (ACC) were investigated using linear regression models. The associations between each of the five personality traits and a latent variable construct of global 5-HT4R levels were also evaluated using latent variable structural equation models. We found no significant associations between the five NEO personality traits and regional 5-HT4R binding (all p-values > .17) or the latent construct of global 5-HT4R levels (all p-values > .37). Our findings indicate that NEO personality traits and 5-HT4R are not related in healthy participants. Under the assumption that global 5-HT4R levels index 5-HT tone, our data also suggest that 5-HT tone per se is not directly implicated in normal personality traits.

Testosterone levels in healthy men correlate negatively with serotonin 4 receptor binding

The serotonergic system integrates sex steroid information and plays a central role in mood and stress regulation, cognition, appetite and sleep. This interplay may be critical for likelihood of developing depressive episodes, at least in a subgroup of sensitive individuals. The serotonin 4 receptor (5-HT4R) indexes central serotonergic tonus, which may be related to endogenous sex-steroid levels in the mentally healthy state even though this remains elusive. Here we evaluate if peripheral levels of estradiol and testosterone are associated with 5-HT4R binding as imaged by [11C]SB207145 positron emission tomography in a group of 41 healthy men. We estimated global 5-HT4R binding using a latent variable model framework, which models shared correlation between 5-HT4R across multiple brain regions (hippocampus, amygdala, posterior and anterior cingulate, thalamus, pallidostriatum and neocortex). We tested whether testosterone and estradiol predict global 5-HT4R, adjusting for age. We found that testosterone, but not estradiol, correlated negatively with global 5-HT4R levels (p=0.02) suggesting that men with high levels of testosterone have higher cerebral serotonergic tonus. Our findings corroborate the link between sex hormone levels and serotonin signalling. Future longitudinal studies in clinical relevant populations are needed to elucidate the potential importance of testosterone in the pathophysiology of e.g. major depression and its treatment.

Brain serotonin 4 receptor binding is associated with the cortisol awakening response

Serotonin signalling is considered critical for an appropriate and dynamic adaptation to stress. Previously, we have shown that prefrontal serotonin transporter (SERT) binding is positively associated with the cortisol awakening response (CAR) (Frokjaer et al., 2013), which is an index of hypothalamic–pituitary–adrenal (HPA)-axis output dynamics. Here, we investigated in healthy individuals if cerebral serotonin 4 receptor (5-HT4r) binding, reported to be a proxy for serotonin levels, is associated with CAR.Thirty healthy volunteers (25 males, age range 20–56 years) underwent 5-HT4r PET imaging with [11C]-SB207145, genotyping of the SERT-linked polymorphic region (5-HTTLPR), and performed serial home sampling of saliva (5 time points from 0 to 60min from awakening) to assess CAR. The association between 5-HT4r binding in 4 regions of interest (prefrontal cortex, anterior cingulate cortex, pallidostriatum, and hippocampus) and CAR was tested using multiple linear regression with adjustment for age and 5-HTTLPR genotype. Finally, an exploratory voxel-based analysis of the association was performed.CAR was negatively associated with 5-HT4r binding in pallidostriatum (p=0.01), prefrontal cortex (p=0.03), and anterior cingulate cortex (p=0.002), respectively, but showed no association in hippocampus. The results remained significant when taking into account other potentially relevant covariates.In conclusion, our finding reinforces an association between HPA-axis function and serotonin signaling in vivo in humans. We suggest that higher synaptic serotonin concentration, here indexed by lower 5-HT4r binding, supports HPA-axis dynamics, which in healthy volunteers is reflected by a robust CAR.

High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding.

Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [(11)C]SB207145 for quantification of brain 5-HT4R binding. The Buss-Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT4R binding were associated with high trait aggression in males, but not in females.

Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: a [11C]SB207145 PET study

Identification of a biomarker that can inform on extracellular serotonin (5-HT) levels in the brains of living humans would enable greater understanding of the way brain circuits are modulated by serotonergic neurotransmission. Substantial evidence from studies in animals and humans indicates an inverse relationship between central 5-HT tonus and 5-HT type 4 receptor (5-HT4R) density, suggesting that 5-HT4R receptor density may be a biomarker marker for 5-HT tonus. Here, we investigated whether a 3-week administration of a selective serotonin reuptake inhibitor, expected to increase brain 5-HT levels, is associated with a decline in brain 5-HT4R binding. A total of 35 healthy men were studied in a placebo-controlled, randomized, double-blind study. Participants were assigned to receive 3 weeks of oral dosing with placebo or fluoxetine, 40 mg per day. Brain 5-HT4R binding was quantified at baseline and at follow-up with [(11)C]SB207145 positron emission tomography (PET). Three weeks of intervention with fluoxetine was associated with a 5.2% reduction in brain 5-HT4R binding (P=0.017), whereas placebo intervention did not change 5-HT4R binding (P=0.52). Our findings are consistent with a model, wherein the 5-HT4R density adjusts to changes in the extracellular 5-HT tonus. Our data demonstrate for the first time in humans that the imaging of central 5-HT4R binding may be used as an in vivo biomarker of the central 5-HT tonus.

Design of fluorinated 5-HT4R antagonists: Influence of the basicity and lipophilicity toward the 5-HT4R binding affinities

Analogues of potent 5-HT4R antagonists possessing a fluorinated N-alkyl chain have been synthesized in order to investigate the effect of the resulting change in basicity and lipophilicity on the affinity and selectivity profile. We demonstrate that for this series, the affinity is decreased with decreased basicity of the piperidine’s nitrogen atom. In contrast, the resulting increase in lipophilicity has minimal impact on binding affinity and selectivity. 3,3,3-Trifluoropropyl and 4,4,4-trifluorobutyl derivatives 6d and 6e have shown to bind to the 5-HT4R while maintaining their pharmacological profile and selectivity toward other 5-HT receptors.

The 5‐HT4 receptor levels in hippocampus correlates inversely with memory test performance in humans

The cerebral serotonin (5-HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5-HT type 4 receptor (5-HT4 R) facilitates memory and learning and further that the 5-HT4 R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5-HT4 R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [(11) C]SB207145 and Reys Auditory Verbal Learning Test we aimed to examine the individual variation of the 5-HT4R binding in hippocampus in relation to memory acquisition and consolidation in healthy young volunteers. We found significant, negative associations between the immediate recall scores and left and right hippocampal BPND , (p = 0.009 and p = 0.010 respectively) and between the right hippocampal BPND and delayed recall (p = 0.014). These findings provide evidence that the 5-HT4 R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory.