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

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

Psychoneuroendocrinology. 2016 Feb 11;67:124-132

Authors: Jakobsen GR, Fisher PM, Dyssegaard A, McMahon B, Holst KK, Lehel S, Svarer C, Jensen PS, Knudsen GM, Frokjaer VG

Abstract
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 [(11)C]-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.

PMID: 26894483 [PubMed – as supplied by publisher]

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Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder.

Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder.

Brain. 2016 Mar 19;

Authors: Mc Mahon B, Andersen SB, Madsen MK, Hjordt LV, Hageman I, Dam H, Svarer C, da Cunha-Bang S, Baaré W, Madsen J, Hasholt L, Holst K, Frokjaer VG, Knudsen GM

Abstract
Cross-sectional neuroimaging studies in non-depressed individuals have demonstrated an inverse relationship between daylight minutes and cerebral serotonin transporter; this relationship is modified by serotonin-transporter-linked polymorphic region short allele carrier status. We here present data from the first longitudinal investigation of seasonal serotonin transporter fluctuations in both patients with seasonal affective disorder and in healthy individuals. Eighty (11)C-DASB positron emission tomography scans were conducted to quantify cerebral serotonin transporter binding; 23 healthy controls with low seasonality scores and 17 patients diagnosed with seasonal affective disorder were scanned in both summer and winter to investigate differences in cerebral serotonin transporter binding across groups and across seasons. The two groups had similar cerebral serotonin transporter binding in the summer but in their symptomatic phase during winter, patients with seasonal affective disorder had higher serotonin transporter than the healthy control subjects (P = 0.01). Compared to the healthy controls, patients with seasonal affective disorder changed their serotonin transporter significantly less between summer and winter (P < 0.001). Further, the change in serotonin transporter was sex- (P = 0.02) and genotype- (P = 0.04) dependent. In the patients with seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom severity, as indexed by Hamilton Rating Scale for Depression – Seasonal Affective Disorder version scores (P = 0.01). Our findings suggest that the development of depressive symptoms in winter is associated with a failure to downregulate serotonin transporter levels appropriately during exposure to the environmental stress of winter, especially in individuals with high predisposition to affective disorders.media-1vid110.1093/brain/aww043_video_abstractaww043_video_abstract.

PMID: 26994750 [PubMed – as supplied by publisher]

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Sex hormone manipulation slows reaction time and increases labile mood in healthy women.

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Sex hormone manipulation slows reaction time and increases labile mood in healthy women.

Psychoneuroendocrinology. 2016 Feb 26;68:39-46

Authors: Stenbæk DS, Fisher PM, Budtz-Jørgensen E, Pinborg A, Hjordt LV, Jensen PS, Knudsen GM, Frokjaer VG

Abstract
BACKGROUND: Women show increased risk of depressive symptoms in life phases where ovarian steroid hormone levels fluctuate or decline rapidly. The risk mechanisms may include changes in mental state and affective cognition possibly mediated by serotonergic neurotransmission.
METHODS: In a randomized controlled double-blinded trial, 61 healthy women (mean age 24.3±4.9 years) were tested with measures of affective verbal memory, reaction time, mental distress, and serotonin transporter binding at baseline and at follow-up after receiving gonadotropin-releasing hormone agonist (GnRHa) or placebo intervention. Women also reported daily mood profiles during intervention. We tested direct effects of intervention and indirect effects through changes in serotonin transporter binding on verbal affective memory, simple reaction time and self-reported measures of mental distress, and further effects of GnRHa on daily mood.
RESULTS: GnRHa induced an increase in simple reaction time (p=0.03) and more pronounced fluctuations in daily self-reported mood in a manner dependent on baseline mood (p=0.003). Verbal affective memory recall, overall self-perceived mental distress, and serotonin transporter binding were not affected.
CONCLUSIONS: In healthy women transient sex-steroid hormone fluctuations decrease speed of information processing and further produce more labile mood only in women with elevated levels of mood disturbances at baseline.

PMID: 26943343 [PubMed – as supplied by publisher]

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Open and Calm–a randomized controlled trial evaluating a public stress reduction program in Denmark.

Open and Calm–a randomized controlled trial evaluating a public stress reduction program in Denmark.

BMC Public Health. 2015;15:1245 Dec.16-2015

Authors: Jensen CG, Lansner J, Petersen A, Vangkilde SA, Ringkøbing SP, Frokjaer VG, Adamsen D, Knudsen GM, Denninger JW, Hasselbalch SG

Abstract
BACKGROUND: Prolonged psychological stress is a risk factor for illness and constitutes an increasing public health challenge creating a need to develop public interventions specifically targeting stress and promoting mental health. The present randomized controlled trial evaluated health effects of a novel program: Relaxation-Response-based Mental Health Promotion (RR-MHP).
METHODS: The multimodal, meditation-based course was publicly entitled “Open and Calm” (OC) because it consistently trained relaxed and receptive (“Open”) attention, and consciously non-intervening (“Calm”) witnessing, in two standardized formats (individual or group) over nine weeks. Seventy-two participants who complained to their general practitioner about reduced daily functioning due to prolonged stress or who responded to an online health survey on stress were randomly assigned to OC formats or treatment as usual, involving e.g., unstandardized consultations with their general practitioner. Outcomes included perceived stress, depressive symptoms, quality of life, sleep disturbances, mental health, salivary cortisol, and visual perception. Control variables comprised a genetic stress-resiliency factor (serotonergic transporter genotype; 5-HTTLPR), demographics, personality, self-reported inattentiveness, and course format.
RESULTS: Intent-to-treat analyses showed significantly larger improvements in OC than in controls on all outcomes. Treatment effects on self-reported outcomes were sustained after 3 months and were not related to age, gender, education, or course format. The dropout rate was only 6 %.
CONCLUSIONS: The standardized OC program reduced stress and improved mental health for a period of 3 months. Further testing of the OC program for public mental health promotion and reduction of stress-related illnesses is therefore warranted. A larger implementation is in progress.
TRIAL REGISTRATION: ClinicalTrials.gov.: NCT02140307. Registered May 14 2014.

PMID: 26673225 [PubMed – in process]

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Evaluation of acute tryptophan depletion and sham depletion with a gelatin-based collagen peptide protein mixture.

Evaluation of acute tryptophan depletion and sham depletion with a gelatin-based collagen peptide protein mixture.

Eur Neuropsychopharmacol. 2015 Nov 26;

Authors: Stenbæk DS, Einarsdottir HS, Goregliad-Fjaellingsdal T, Knudsen GM, Frokjaer VG, Hasselbalch SG

Abstract
Acute Tryptophan Depletion (ATD) is a dietary method used to modulate central 5-HT to study the effects of temporarily reduced 5-HT synthesis. The aim of this study is to evaluate a novel method of ATD using a gelatin-based collagen peptide (CP) mixture. We administered CP-Trp or CP+Trp mixtures to 29 healthy volunteers; 13 from a randomized, double-blinded crossover study and sixteen from a randomized, double-blinded study run in our laboratory. Plasma amino acids, mood, side effects, cortisol concentrations, mean arterial blood pressure and heart rate were measured at multiple time-points. Repeated measures analysis of variance and Wilcoxon or Mann-Whitney U non-parametric tests were used to analyze the effects of intervention. Intake of the CP-Trp mixture efficiently reduced plasma Trp; however, the CP+Trp mixture induced a large significant increase in plasma Trp. No other significant effects of CP-Trp compared to CP+Trp were observed. The transient increase in plasma Trp after CP+Trp may impair comparison to the CP-Trp and we therefore recommend in future studies to use a smaller dose of Trp supplement to the CP mixture.

PMID: 26655163 [PubMed – as supplied by publisher]

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Fluctuations in [¹¹C]SB207145 PET binding associated with change in threat-related amygdala reactivity in humans.

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Fluctuations in [¹¹C]SB207145 PET binding associated with change in threat-related amygdala reactivity in humans.

Neuropsychopharmacology. 2015 May;40(6):1510-8

Authors: Fisher PM, Haahr ME, Jensen CG, Frokjaer VG, Siebner HR, Knudsen GM

Abstract
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 [(11)C]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 [(11)C]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 [(11)C]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 [(11)C]SB207145 binding, a putative marker of brain serotonin levels, affect amygdala reactivity to threat. Our finding also supports that change in brain [(11)C]SB207145 binding may be a relevant marker for evaluating neurobiological mechanisms underlying sensitivity to threat and serotonin signaling.

PMID: 25560201 [PubMed – in process]

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Role of emotional processing in depressive responses to sex-hormone manipulation: a pharmacological fMRI study.

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Role of emotional processing in depressive responses to sex-hormone manipulation: a pharmacological fMRI study.

Transl Psychiatry. 2015;5:e688

Authors: Henningsson S, Madsen KH, Pinborg A, Heede M, Knudsen GM, Siebner HR, Frokjaer VG

Abstract
Sex-hormone fluctuations may increase risk for developing depressive symptoms and alter emotional processing as supported by observations in menopausal and pre- to postpartum transition. In this double-blinded, placebo-controlled study, we used blood-oxygen level dependent functional magnetic resonance imaging (fMRI) to investigate if sex-steroid hormone manipulation with a gonadotropin-releasing hormone agonist (GnRHa) influences emotional processing. Fifty-six healthy women were investigated twice: at baseline (follicular phase of menstrual cycle) and 16 ± 3 days post intervention. At both sessions, fMRI-scans during exposure to faces expressing fear, anger, happiness or no emotion, depressive symptom scores and estradiol levels were acquired. The fMRI analyses focused on regions of interest for emotional processing. As expected, GnRHa initially increased and subsequently reduced estradiol to menopausal levels, which was accompanied by an increase in subclinical depressive symptoms relative to placebo. Women who displayed larger GnRHa-induced increase in depressive symptoms had a larger increase in both negative and positive emotion-elicited activity in the anterior insula. When considering the post-GnRHa scan only, depressive responses were associated with emotion-elicited activity in the anterior insula and amygdala. The effect on regional activity in anterior insula was not associated with the estradiol net decline, only by the GnRHa-induced changes in mood. Our data implicate enhanced insula recruitment during emotional processing in the emergence of depressive symptoms following sex-hormone fluctuations. This may correspond to the emotional hypersensitivity frequently experienced by women postpartum.

PMID: 26624927 [PubMed – in process]

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Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer’s disease: a combined [11C]DASB and [18F]altanserin-PET study.

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Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer’s disease: a combined [11C]DASB and [18F]altanserin-PET study.

Neurobiol Aging. 2012 Mar;33(3):479-87

Authors: Marner L, Frokjaer VG, Kalbitzer J, Lehel S, Madsen K, Baaré WF, Knudsen GM, Hasselbalch SG

Abstract
In patients with Alzheimer’s disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT(2A)) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT(2A) receptor and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [(18)F]altanserin and [(11)C]N,N-Dimethyl-2-(2-amino-4-cyanopheylthio)benzylamine ([(11)C]DASB). Overall [(18)F]altanserin binding was markedly reduced in AD by 28%-39% (p = 0.02), whereas the reductions in [(11)C]DASB binding were less prominent and mostly insignificant, except for a marked reduction of 33% in mesial temporal cortex (p = .0005). No change in [(11)C]DASB binding was found in the midbrain. We conclude that the prominent reduction in neocortical 5-HT(2A) receptor binding in early AD is not caused by a primary loss of serotonergic neurons or their projections.

PMID: 20510480 [PubMed – indexed for MEDLINE]

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Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer’s disease: a combined [11C]DASB and [18F]altanserin-PET study.

Related Articles

Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer’s disease: a combined [11C]DASB and [18F]altanserin-PET study.

Neurobiol Aging. 2012 Mar;33(3):479-87

Authors: Marner L, Frokjaer VG, Kalbitzer J, Lehel S, Madsen K, Baaré WF, Knudsen GM, Hasselbalch SG

Abstract
In patients with Alzheimer’s disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT(2A)) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT(2A) receptor and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [(18)F]altanserin and [(11)C]N,N-Dimethyl-2-(2-amino-4-cyanopheylthio)benzylamine ([(11)C]DASB). Overall [(18)F]altanserin binding was markedly reduced in AD by 28%-39% (p = 0.02), whereas the reductions in [(11)C]DASB binding were less prominent and mostly insignificant, except for a marked reduction of 33% in mesial temporal cortex (p = .0005). No change in [(11)C]DASB binding was found in the midbrain. We conclude that the prominent reduction in neocortical 5-HT(2A) receptor binding in early AD is not caused by a primary loss of serotonergic neurons or their projections.

PMID: 20510480 [PubMed – indexed for MEDLINE]

Source: My publications feed from NCBI