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.

Familial risk for major depression is associated with lower striatal 5-HT4 receptor binding.

BACKGROUND: The 5-HT4 receptor provides a novel potential target for antidepressant treatment. No studies exist to elucidate the 5-HT4 receptor's in vivo distribution in the depressed state or in populations that may display trait markers for major depression disorder (MDD). The aim of this study was to determine whether familial risk for MDD is associated with cerebral 5-HT4 receptor binding as measured with [(11)C]SB207145 brain PET imaging. Familial risk is the most potent risk factor of MDD. METHODS: We studied 57 healthy individuals (mean age 36 yrs, range 20-86; 21 women), 26 of which had first-degree relatives treated for MDD. RESULTS: We found that having a family history of MDD was associated with lower striatal 5-HT4 receptor binding (p = 0.038; in individuals below 40 years, p = 0.013). Further, we found evidence for a "risk-dose effect" on 5-HT4 receptor binding, since the number of first-degree relatives with a history of MDD binding correlated negatively with 5-HT4 receptor binding in both the striatum (p = 0.001) and limbic regions (p = 0.012). CONCLUSIONS: Our data suggest that the 5-HT4 receptor is involved in the neurobiological mechanism underlying familial risk for depression, and that lower striatal 5-HT4 receptor binding is associated with increased risk for developing MDD. The finding is intriguing considering that the 5-HT4 receptor has been suggested to be an effective target for antidepressant treatment.

5-HTTLPR status predictive of neocortical 5-HT4 binding assessed with [(11)C]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.

No change in [¹¹C]CUMI-101 binding to 5-HT(1A) 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-HT(1A) 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.

Personality characteristics in surgery seeking and non-surgery seeking obese individuals compared to non-obese controls.

It is currently unknown what makes some obese individuals opt for bariatric surgery whereas others choose not to. The aim of this study was to examine whether personality characteristics differed between obese individuals signed up for Roux-en-Y gastric bypass (RYGB) (N=30) and obese individuals not seeking RYGB (N=30) compared to non-obese controls (N=30). All participants completed the NEO Personality Inventory-Revised. The obese RYGB group displayed higher levels of Neuroticism and borderline lower levels of Extraversion compared to the obese non-RYGB and the non-obese group, while the two latter groups did not differ in terms of personality. The Neuroticism domain and possibly the Extraversion domain may therefore be worthwhile to consider in future studies investigating the outcome of bariatric surgery.

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

Depressive symptoms are frequent in Alzheimer's disease (AD), but it is controversial whether depression is a risk factor for AD. This study measured for the first time cortical amyloid-ß (Aß) 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.

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-HT(2A) and 5-HT(4) 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-HT(4) and 5-HT(2A) 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-HT(2A) 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.