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IntroductionIt has been shown that patients with schizophrenia are super-sensitive towards dopamine-releasing agents such as amphetamine. Here, we studied the effects of amphetamine sensitization on amphetamine-induced dopamine release in healthy subjects.ObjectivesTo measure d-amphetamine-induced dopamine release as measured with the D2,3 agonist radioligand [11C]-(+)-PHNO-PET via change in non-displacable binding potential (BPND) and behavioral measures of d-amphetamine effects with drug effects questionnaire (DEQ) and subjective states questionnaire (SSQ).AimsTo study d-amphetamine-induced sensitization in healthy subjects on a behavioral and neurochemical level with [11C]-(+)-PHNO-PET in order to gain more knowledge on sensitization-induced changes in the dopaminergic system.MethodsTwelve stimulant-naïve healthy male subjects underwent three 90-min [11C]-(+)-PHNO-PET-scans and four oral administrations of d-amphetamine. After a naïve baseline scan, subjects underwent a PET scan with previous ingestion of 0.4 mg/kg bodyweight of d-amphetamine 90–120 minutes before scanning. Subsequently, subjects were sensitized to d-amphetamine with the same dose on two separate days. Thereafter, they underwent another PET scan with previous d-amphetamine ingestion. DEQ and SSQ were administered before, 60 min, 90–120 min, and 210 min after amphetamine ingestion.ResultsWe found significant sensitization effects on a behavioral level and on a neurochemical level after four administrations of amphetamine. Items of the SSQ, which showed significant sensitization effects were “outgoing”, “energetic”, “lively”, “alert” and “focused”.ConclusionsWe were able to induce significant behavioral and neurochemical sensitization in healthy humans, which were measured with [11C]-(+)-PHNO-PET for the first time. This sensitization model will be useful for studying the neurobiology of schizophrenia.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Introduction The serotonergic system modulates brain functions that are considered to underlie affective states, emotion and cognition. Several lines of evidence point towards a strong lateralization of these mental processes, indicating similar asymmetries in associated neurotransmitter systems. Objectives To investigate a potential brain asymmetry of the serotonin transporter (SERT) distribution using Positron Emission Tomography (PET). Aims As brain asymmetries differ between sexes, we aimed to compare serotonin transporter asymmetry between females, males and male-to-female transsexuals whose brains are considered to be partly feminized. Methods 36 subjects aged 19-54 years (9 female controls, 13 male controls and 14 male-to-female transsexuals) were measured with PET and [ 11 C]DASB. Whole-brain voxel-wise SERT binding potential (BP ND ) maps were computed using a tracer-specific symmetric template. Statistics comprised repeated measures ANOVA with group as the between subjects factor, voxel-wise SERT asymmetry as repeated factor and group*asymmetry as interaction term. Results SERT binding in all groups showed both strong left and rightward asymmetries in several cortical and subcortical structures including temporal and frontal cortices, anterior cingulate, hippocampus, caudate and thalamus (p 0.05 FDR-corrected) which was absent in females and male-to-female transsexuals. Conclusions Our data support the notion of a lateralized serotonergic system, which is in line with previous findings of asymmetric serotonin-1A receptor distributions, extracellular serotonin concentrations, serotonin turnover and uptake. The absence of serotonin transporter asymmetry in the midcingulate in male-to-female transsexuals may be attributed to an absence of brain masculinization in this region.

Introduction Dysfunctional neuroplasticity contributes to the pathogenesis of Alzheimer's disease, schizophrenia and depression. However, the underlying molecular mechanisms are not fully understood. Previous studies report neuromodulatory properties of the serotonin-1A (5-HT 1A ) receptor, which is also altered in these disorders. This suggests 5-HT 1A mediated neuroplasticity as potential pathogenic factor. Objectives The aim of this study was to demonstrate 5-HT 1A mediated neuroplasticity in vivo. Methods We used positron emission tomography to quantify 5-HT 1A receptor binding (BP ND ) together with structural magnetic resonance imaging in 35 healthy subjects (mean 26.6 ±6.8 years; 17 women). Voxel-wise regression analysis was performed with gray matter volume (GMV) as dependent and 5-HT 1A BP ND as independent variable. Additionally, regression analysis was calculated with whole brain GMV as dependent variable and 5-HT 1A BP ND of the dorsal raphe nucleus (DRN) as independent variable. Control variables were age, sex and total GMV, respectively. Results 5-HT 1A receptor density predicted GMV of the hippocampus, medial temporal cortex, inferior temporal cortex, medial occipital cortex and the pericalcarine region in each hemisphere (p R 2 : 0.308–0.503). These associations were independent from local numbers of neurons. Furthermore, 5−HT 1A receptor levels in the DRN predicted GMV of the anterior cingulate cortex (p = 0.001, R 2 =0.656, uncorrected). Conclusions These results demonstrate 5-HT 1A receptor mediated morphogenetic mechanisms in healthy human subjects' brains, which occur not only locally but also at the macro-network level. Finally, morphogenetic signaling investigated with multimodal neuroimaging could contribute to better understanding and diagnostic identification of gray matter loss in neuropsychiatric disorders.

IntroductionThe subgenual part of the anterior cingulate cortex (sgACC) has been frequently reported to be structurally and cytoarchitectually changed in major depressive disorder (MDD) and is also a promising target in deep brain stimulation in treatment-resistant MDD. Furthermore, substantial evidence demonstrates a high density of serotonin-1A (5-HT1A) receptors in the sgACC, a key area involved in emotional processing.ObjectivesHere, we investigated the relationship between the 5-HT1A receptor in the sgACC and changes in regional grey matter volume with voxel-based morphometry.MethodsPET ([carbonyl-11C]WAY-100635) was used to quantify 5-HT1A receptor binding (BPND) together with structural magnetic resonance images from 32 healthy subjects (mean 26.68 ± 5.1 years; 17 women). Regression analysis was performed in SPM8 (p < .001 uncorr.) using sgACC 5-HT1A BPND as regressor, controlling for sex, age and total grey matter volume (GMV).Results5-HT1A BPND in the sgACC was positively associated with regional GMV in the medial temporal gyri (T=4.37) and nucleus accumbens bilaterally (T = 4.19). Furthermore, sgACC 5-HT1A binding was negatively correlated with GMV within the inferior temporal gyri (T = 5.22) and putamen bilaterally (T = 5.12).ConclusionsOur findings demonstrate structural relationships between sgACC 5-HT1A receptor binding and grey matter volume in the ventral striatum as well as in temporal regions, which both exhibit close neuronal connections with the sgACC. Moreover, the GMV of the ventral striatum has been reported to be decreased in patients with MDD. Conclusively, our results underpin the role of serotonergic neuronal transmission in cytoarchitectural processes within regions involved in the modulation of mood.

IntroductionRegional alterations of serotonergic neurotransmission and functional activation in the amygdalar region of patients with major depression are underpinning its important role in affective disorders. In this study we used fMRI and PET to describe functional and molecular alterations associtated with an astrocytoma in the left amygdalar region in a patient with organic depressive disorder compared to control subjects.MethodsThe serotonin-1A (5-HT1A) receptor binding (BPND) was quantified with PET (30 frames, 90 min, 4.4 mm FWHM) in 36 subjects using the radioligand [carbonyl-11C]WAY-100635, and a reference tissue model (MRTM2). In fMRI (3T, EPI inplane resolution 1.6*2.7 mm, 10 AC-PC orientated slices, ST = 3 mm, TE/TR = 31/1000 ms), 32 participants performed emotion discrimination and sensorimotor control tasks. Statistical analysis with SPM5 and unpaired t-tests were performed on molecular and functional data separately.ResultsThe astrocytoma was delineated in the serotonin-1A receptor distribution showing (p < 0.01, uncorrected) regional BPND decrease. The ipsilateral thalamus and bilateral habenula regions displayed (p < 0.001; uncorrected) BPND increase. The fMRI data showed significantly (p < 0.05; uncorrected) reduced activation in the affected amygdalar region, ipsilateral fusiform gyrus, bilateral orbitofrontal cortex and temporal regions and increased activation in the contralateral temporal pole.ConclusionsLower serotonin-1A receptor binding in the left amydala region reflects the glial provenance of the tumor. The increased receptor binding in the habenulae might be associated with altered monoaminergic neurotransmission and depressive symptoms according to the influence of the habenulae on monoaminergic nuclei. The functional data demonstrate neuroplastic changes beyond affected areas and might indicate compensatory mechanisms.

IntroductionBased on evidences in molecular neuroimaging, postmortem and genetic studies, impaired serotonergic neurotransmission has been implicated with affective disorders. Moreover, a growing number of evidences showed strong interrelations within the serotonergic system suggesting a common mechanism in the modulation of receptor and transporter densities.ObjectiveHere we directly investigated the regional expression of the 5-HT1A, 5-HT2A and 5-HTT using PET and the three highly selective and specific radioligands [carbonyl-11C]WAY-100635, [18F]Altanserin and [11C]DASB in healthy subjects.MethodsA total of 55 healthy subjects (5-HT1A: 36 subjects, 18 males, age = 26.0 ± 4.9; 5-HT2A: 19 subjects, 11 males, age = 28.2 ± 5.9; 5-HTT: 8 males, age = 28.12 ± 3.6) were included in this study. Binding potential (BPND) values were quantified according to the AAL parcellation scheme.ResultsBPND values averaged over both hemispheres ranged from 0.40–6.35 for the 5-HT1A receptor; 0.01–2.01 for the 5-HT2A receptor and 0.09–2.05 for the 5-HTT, respectively. There was a specific topological pattern according to the ratio between the 5-HT1A, 5-HT2A receptors and 5-HTT (“fingerprints”).ConclusionsSuch information can be essential for detecting potential local alterations in the ratio between different binding proteins on a network level in pathological conditions.Moreover, these data might provide further insight in area-specific effects of frequently prescribed selective serotonin re-uptake inhibitors (SSRI): 1)due to the distinct local receptor and transporter availability;2)SSRI application alters the postsynaptic receptor expression and thus;3)leads to a modified interaction of inhibitory and exhibitory receptors.

IntroductionPatients suffering from major depressive disorder (MDD) exhibit alterations in serotonin transporter (5-HTT) binding clinically reflected by lack of hedonic experience. We recently demonstrated the importance to evaluate interregional relationships of neurotransmitter systems, providing important complementary information on a network level.ObjectiveTo identify interregional 5-HTT relationships between the midbrain raphe region and projection areas in MDD patients compared to controls.MethodsEighteen medication-free patients with MDD and 16 healthy subjects underwent PET using [11C] DASB. 5-HTT binding potential (BPND) maps were computed with the multilinear-reference-tissue-model-2 in PMOD3.1. Voxel-wise linear regression was calculated in SPM8 using midbrain 5-HTT BPND as regressor; group comparisons were assessed by ANOVA (p < 0.001).ResultsHealthy subjects showed positive associations between serotonin transporters located in the midbrain and transporters expressed in the nucleus accumbens bilaterally. Importantly, this relationship was significantly decreased in MDD patients as compared to controls (t = 5.41/4.84, right/left hemisphere; see figure).ConclusionsThis study demonstrates for the first time 5-HTT alterations on a network level in MDD patients between the midbrain and a major projection area. Our results complement previous findings emphasizing the importance of the nucleus accumbens in MDD and indicate a disturbed serotonergic regulation in this key area of reward processing.

IntroductionClinical studies point toward a potential role of the serotonin transporter (SERT) binding as a predictor of clinical outcome in the treatment of depression. After long-term treatment with clinical doses of SSRIs the expected SERT occupancy is about 80%. Here, we were interested to investigate the relationship of SERT occupancy values between short- and longterm treatment.ObjectivesTo test if the SERT occupancy at steady-state can be predicted based on the single dose occupancy by escitalopram (S-citalopram) or citalopram (racemate of S-citalopram and R-citalopram).Methods18 patients with major depressive disorder received either escitalpram (10 mg/d) or citalopram (20 mg/d) in a double-blind, randomized, longitudinal study. They underwent three PET scans using the radioligand [11C]DASB: PET1 baseline, PET2 6 hours after first drug intake and PET3 after three weeks of daily oral treatment. Occupancy of SERT was quantified in six subcortical regions: thalamus, N. caudatus, putamen, mibrain, dorsal raphe and median raphe nuclei. Data was analyzed by means of multiple linear regression models corrected for baseline SERT availability values using SPSS 15.0.ResultsSingle dose occupancy of the SERT significantly predicted steady-state occupancy after three weeks in three regions: thalamus (r2 = 0.45, p = 0.009), N. caudatus (r2 = 0.4, p = 0.006) and putamen (r2 = 0.43, p = 0.005). Other regions did not show significant relationships.ConclusionsIn this study we demonstrated that single-dose occupancy in SERT rich regions such as thalamus, N. caudatus and the putamen could serve as reliable predictors for steady-state occupancy. However, a linear model failed to explain the relationship in regions known for serotonergic cell origin.

IntroductionAlterations of the serotonin-1A receptor (5-HT1A) and the hypothalamic-pituitary-adrenal (HPA) axis have been reported in depression and anxiety disorders. We previously showed a strong negative correlation between cortisol plasma levels and 5-HT1A receptor binding potential (BP) in patients with social anxiety disorder but not in healthy controls using PET [1].ObjectivesTo investigate the relationship of cortisol and the 5-HT1A BP in postmenopausal women, a population that is at increased risk of suffering from depressive symptoms.MethodsSubjects: 19 postmenopausal women, aged 55.26 ± 4.98, medication free, no current substance abuse or hormone replacement therapy.PETDynamic measurements (50 frames, 90 min) were performed using the radioligand [carbonyl-11C]WAY100635 and a GE-Advance scanner. PET data were normalized to a ligand-specific template [2]. Regions-of-interest (ROI) were defined as given in [3]. TACs within ROIs were averaged and the 5-HT1A receptor BP was quantified using Logan-plot and PMOD 3.1. Measurement of total cortisol plasma levels was done using electrochemoluminescence.ResultsWe found negative correlations between cortisol and 5-HT1A BP in the midbrain (Spearman's rs = −0.54, p = 0.02), the median raphe nucleus (rs = −0.47, p = 0.04) and the nucleus accumbens (rs = −0.505, p = 0.03).ConclusionsIn line with our previous findings [1], the observed negative association between cortisol plasma levels and 5-HT1A BP might reflect an increased vulnerability for mood disorders in postmenopausal women.

ObjectivesSerotonergic neurotransmission plays a key role in seasonal changes of mood and behaviour. Higher serotonin transporter availability in healthy human subjects in times of lesser light has been reported in recent studies. Furthermore, seasonal alterations of postsynaptic serotonin-1A receptors have been suggested by a recent animal study. Following that, this study aimed at identifying seasonal alterations of serotonin-1A receptor binding in the living human brain.MethodsThirty-six healthy, drug-naïve subjects were investigated using PET and the specific tracer [carbonyl-11C]WAY-100635. Regional serotonin-1A receptor binding (5-HT1A BPND) was related to the individual exposure to global radiation. Furthermore, the subjects were divided into two groups depending on individual exposure to global radiation, and the group differences in regional 5-HT1A BPND were determined.ResultsCorrelation analysis controlled for age and gender revealed highly significant positive correlations between regional postsynaptic 5-HT1A BPND and global radiation accumulated for 5 days (r=.32 to .48, p=.030 to .002). Highly significant differences in 5-HT1A BPND binding between subjects with low compared to high exposure to global radiation were revealed (T=-2.63 to -3.77, p .013 to .001). 20% to 30% lower 5-HT1A BPND was found in the subject group exposed to lower amount of global radiation.ConclusionSeasonal factors such as exposure to global radiation influence postsynaptic serotonin-1A receptor binding in various brain regions in healthy human subjects. In combination with seasonal alterations in serotonin turnover and 5-HTT availability revealed in recent studies, our results provide an essential contribution of molecular mechanisms in seasonal changes of human serotonergic neurotransmission.