Mette E. Haahr

Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

The neurobiology underlying obesity is not fully understood. The neurotransmitter serotonin (5-HT) is established as a satiety-generating signal, but its rewarding role in feeding is less well elucidated. From animal experiments there is now evidence that the 5-HT(4) receptor (5-HT(4)R) is involved in food intake, and that pharmacological or genetic manipulation of the receptor in reward-related brain areas alters food intake. Here, we used positron emission tomography in humans to examine the association between cerebral 5-HT(4)Rs and common obesity. We found in humans a strong positive association between body mass index and the 5-HT(4)R density bilaterally in the two reward ‘hot spots’ nucleus accumbens and ventral pallidum, and additionally in the left hippocampal region and orbitofrontal cortex. These findings suggest that the 5-HT(4)R is critically involved in reward circuits that regulate peoples food intake. They also suggest that pharmacological stimulation of the cerebral 5-HT(4)R may reduce reward-related overeating in humans.

Lack of association between prior depressive episodes and cerebral [11C]PiB binding

Depressive symptoms are frequent in Alzheimers disease (AD), but it is controversial whether depression is a risk factor for AD. This study measured for the first time cortical amyloid-β (Aβ) levels using [(11)C] Pittsburgh Compound B (PiB) positron emission tomography (PET) in a group of nondemented patients with prior depressive episodes. Twenty-eight elderly patients (mean age 61 years, range 51-75, 18 women) with onset of first depressive episode more than 6 years ago but now remitted from depression and 18 healthy subjects (mean age 61 years, range 50-76, 12 women) were included. All subjects were investigated with cognitive testing, 3T magnetic resonance imaging (MRI) and [(11)C]PiB high resolution research tomography (HRRT) positron emission tomography scan. There was no between-groups difference in [(11)C]PiB binding (p = 0.5) and no associations to number of depressive episodes, cognitive performance, or antidepressant treatment. Patients with late onset of depression had increased severity of white matter lesions (p = 0.04). In this study depressive episodes were not associated with increased levels of [(11)C]PiB. Thus, our results do not support the notion that depressive episodes previously in life are a risk factor for developing AD.

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 [11C]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.

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‐HT4R) facilitates memory and learning and further that the 5‐HT4R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5‐HT4R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [11C]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‐HT4R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory. Hum Brain Mapp 34:3066–3074, 2013.

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

Serotonin (5-HT) is a neuromodulator affecting myriad aspects of personality and behavior and has been implicated in the pathophysiology of affective disorders including depression and anxiety. The 5-HTTLPR is a common genetic polymorphism within the promoter region of the gene coding for the serotonin transporter such that the S allele is associated with reduced transcriptional efficacy compared to the L allele, potentially contributing to increased serotonin levels. In humans, this genetic variant has been linked to inter-individual variability in risk for affective disorders, related aspects of personality and brain function including response to threat. However, its effects on aspects of serotonin signaling in humans are not fully understood. Studies in animals suggest that the 5-HT 4 receptor (5-HT(4)) shows a monotonic inverse association with long-term changes in serotonin levels indicating that it may be a useful measure for identifying differences in serotonergic neurotransmission. In 47 healthy adults we evaluated the association between 5-HTTLPR status and in vivo 5-HT(4) receptor binding assessed with [(11)C]SB207145 positron emission tomography (PET). We observed a significant association within the neocortex where [(11)C]SB207145 binding was 9% lower in S carriers compared to LL homozygotes. We did not find evidence for an effect of season or a season-by-5-HTTLPR interaction effect on regional [(11)C]SB207145 binding. Our findings are consistent with a model wherein the 5-HTTLPR S allele is associated with relatively increased serotonin levels. These findings provide novel evidence supporting an effect of 5-HTTLPR status on serotonergic neurotransmission in adult humans. There were no indications of seasonal effects on serotonergic neurotransmission.

Central 5-HT neurotransmission modulates weight loss following gastric bypass surgery in obese individuals.

The cerebral serotonin (5-HT) system shows distinct differences in obesity compared with the lean state. Here, it was investigated whether serotonergic neurotransmission in obesity is a stable trait or changes in association with weight loss induced by Roux-in-Y gastric bypass (RYGB) surgery. In vivo cerebral 5-HT2A receptor and 5-HT transporter binding was determined by positron emission tomography in 21 obese [four men; body mass index (BMI), 40.1 ± 4.1 kg/m2] and 10 lean (three men; BMI, 24.6 ± 1.5 kg/m2) individuals. Fourteen obese individuals were re-examined after RYGB surgery. First, it was confirmed that obese individuals have higher cerebral 5-HT2A receptor binding than lean individuals. Importantly, we found that higher presurgical 5-HT2A receptor binding predicted greater weight loss after RYGB and that the change in 5-HT2A receptor and 5-HT transporter binding correlated with weight loss after RYGB. The changes in the 5-HT neurotransmission before and after RYGB are in accordance with a model wherein the cerebral extracellular 5-HT level modulates the regulation of body weight. Our findings support that the cerebral 5-HT system contributes both to establish the obese condition and to regulate the body weight in response to RYGB.

No change in [11C]CUMI-101 binding to 5-HT1A receptors after intravenous citalopram in human

The main objective of this study was to determine the sensitivity of [11C]CUMI‐101 to citalopram challenge aiming at increasing extracellular 5‐HT. CUMI‐101 has agonistic properties in human embryonic kidney 293 cells transfected with human recombinant 5‐HT1A receptors (Hendry et al. [2011] Nucl Med Biol 38:273–277; Kumar et al. [2006] J Med Chem 49:125–134) and has previously been demonstrated to be sensitive to bolus citalopram in monkeys (Milak et al. [2011] J Cereb Blood Flow Metab 31:243–249). We studied six healthy individuals. Two PET‐scans were performed on the same day in each individual before and after constant infusion of citalopram (0.15 mg/kg). The imaging data were analyzed using two tissue compartment kinetic modeling with metabolite corrected arterial input and Simplified Reference Tissue Modeling using cerebellum as a reference region. There was no significant difference in regional distribution volume or non‐displaceable binding potential values before and after citalopram infusion. The mean receptor occupancy was 0.03 (range −0.14 to 0.17). Our data imply that [11C]CUMI‐101 binding is not sensitive to citalopram infusion in humans. Synapse, 2012.

cerebral Markers of the Serotonergic System in Rat Models of Obesity and After Roux-en-Y Gastric Bypass

Food intake and body weight are regulated by a complex system of neural and hormonal signals, of which the anorexigenic neurotransmitter serotonin (5‐hydroxytryptamine or 5‐HT) is central. In this study, rat models of obesity and weight loss intervention were compared with regard to several 5‐HT markers. Using receptor autoradiography, brain regional‐densities of the serotonin transporter (SERT) and the 5‐HT2A and 5‐HT4 receptors were measured in (i) selectively bred polygenic diet‐induced obese (pgDIO) rats, (ii) outbred DIO rats, and (iii) Roux‐en‐Y gastric bypass (RYGB)–operated rats. pgDIO rats had higher 5‐HT4 and 5‐HT2A receptor binding and lower SERT binding when compared to polygenic diet‐resistant (pgDR) rats. The most pronounced difference between pgDIO and pgDR rats was observed in the nucleus accumbens shell (NAcS), a brain region regulating reward aspects of feeding. No differences were found in the 5‐HT markers between DIO rats, chow‐fed control rats, and DIO rats experiencing a weight loss. The 5‐HT markers were also similar in RYGB and sham‐operated rats except for a downregulation of 5‐HT2A receptors in the NAcS. The higher receptor and lower SERT binding in pgDIO as compared to pgDR rats corresponds to what is reported in overweight humans and suggests that the dysfunctions of the 5‐HT system associated with overeating or propensity to become overweight are polygenically determined. Our results support that the obesity‐prone rat model has high translational value and suggests that susceptibility to develop obesity is associated with changed 5‐HT tone in the brain that may also regulate hedonic aspects of feeding.

Fluctuations in [11C]SB207145 PET Binding Associated with Change in Threat-Related Amygdala Reactivity in Humans

Serotonin critically affects the neural processing of emotionally salient stimuli, including indices of threat; however, how alterations in serotonin signaling contribute to changes in brain function is not well understood. Recently, we showed in a placebo-controlled study of 32 healthy males that brain serotonin 4 receptor (5-HT4) binding, assessed with [11C]SB207145 PET, was sensitive to a 3-week intervention with the selective serotonin reuptake inhibitor fluoxetine, supporting it as an in vivo model for fluctuations in central serotonin levels. Participants also underwent functional magnetic resonance imaging while performing a gender discrimination task of fearful, angry, and neutral faces. This offered a unique opportunity to evaluate whether individual fluctuations in central serotonin levels, indexed by change in [11C]SB207145 binding, predicted changes in threat-related reactivity (ie, fear and angry vs neutral faces) within a corticolimbic circuit including the amygdala and medial prefrontal and anterior cingulate cortex. We observed a significant association such that decreased brain-wide [11C]SB207145 binding (ie, increased brain serotonin levels) was associated with lower threat-related amygdala reactivity, whereas intervention group status did not predict change in corticolimbic reactivity. This suggests that in the healthy brain, interindividual responses to pharmacologically induced and spontaneously occurring fluctuations in [11C]SB207145 binding, a putative marker of brain serotonin levels, affect amygdala reactivity to threat. Our finding also supports that change in brain [11C]SB207145 binding may be a relevant marker for evaluating neurobiological mechanisms underlying sensitivity to threat and serotonin signaling.

Effects of selective serotonin reuptake inhibition on neural activity related to risky decisions and monetary rewards in healthy males.

Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are commonly prescribed antidepressant drugs targeting the dysfunctional serotonin (5-HT) system, yet little is known about the functional effects of prolonged serotonin reuptake inhibition in healthy individuals. Here we used functional MRI (fMRI) to investigate how a three-week fluoxetine intervention influences neural activity related to risk taking and reward processing. Employing a double-blinded parallel-group design, 29 healthy young males were randomly assigned to receive 3 weeks of a daily dose of 40 mg fluoxetine or placebo. Participants underwent task-related fMRI prior to and after the three-week intervention while performing a card gambling task. The task required participants to choose between two decks of cards. Choices were associated with different risk levels and potential reward magnitudes. Relative to placebo, the SSRI intervention did not alter individual risk-choice preferences, but modified neural activity during decision-making and reward processing: During the choice phase, SSRI reduced the neural response to increasing risk in lateral orbitofrontal cortex, a key structure for value-based decision-making. During the outcome phase, a midbrain region showed an independent decrease in the responsiveness to rewarding outcomes. This midbrain cluster included the raphe nuclei from which serotonergic modulatory projections originate to both cortical and subcortical regions. The findings corroborate the involvement of the normally functioning 5HT-system in decision-making under risk and processing of monetary rewards. The data suggest that prolonged SSRI treatment might reduce emotional engagement by reducing the impact of risk during decision-making or the impact of reward during outcome evaluation.