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

ABSTRACT: 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 (BP_ND) 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 BP_ND 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.

SUBMITTER: Sankar A

PROVIDER: S-EPMC10175268 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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

Sankar Anjali A Ozenne Brice B Dam Vibeke H VH Svarer Claus C Jørgensen Martin B MB Miskowiak Kamilla W KW Frokjaer Vibe G VG Knudsen Gitte M GM Fisher Patrick M PM

Translational psychiatry 20230511 1

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-HT<sub>4</sub> receptor (5-HT<sub>4</sub>R) levels, a promising target for antidepressant treatment. However, how these alterations influence neural processing of emotions in MDD remains poorly understoo ...[more]

PMID: 37169780

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Project description:There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n=71), aged 20-80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [(11)C]WAY100635 and [(18)F]altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (V(T)) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age(2), sex, and hormone concentrations, with post hoc regional significance set at p<0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p=0.004-0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p=0.05-0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p=0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p=0.03-0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; p<0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low hormone concentrations in adults <50 years of age may be associated with more extreme 5HT1A receptor BP values, but remains to be studied further. The 5HT2A receptor declines with age were not related to sex or hormone concentrations in this sample. Additional study in clinical populations is needed to further examine the affective role of sex-hormone-serotonin receptor relationships.

Dataset Information

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

Publications

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

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