The influence of the moisture content of microcrystalline cellulose on the coating process in a fluidized bed

Overweight and obesity is a health threat of increasing concern and understanding the neurobiology behind obesity is instrumental to the development of effective treatment regimes. Serotonergic neurotransmission is critically involved in eating behaviour; cerebral level of serotonin (5-HT) in animal models is inversely related to food intake and body weight and some effective anti-obesity agents involve blockade of the serotonin transporter (SERT). We investigated in 60 healthy volunteers body mass index (BMI) and regional cerebral SERT binding as measured with [(11)C]DASB PET. In a linear regression model with adjustment for relevant covariates, we found that cortical and subcortical SERT binding was negatively correlated to BMI (-0.003 to -0.012 BP(ND) unit per kg/m(2)). Tobacco smoking and alcohol consumption did not affect cerebral SERT binding. Several effective anti-obesity drugs encompass blockade of the SERT; yet, our study is the first to demonstrate an abnormally decreased cerebral SERT binding in obese individuals. Whether the SERT has a direct role in the regulation of appetite and eating behaviour or whether the finding is due to a compensatory downregulation of SERT secondary to other dysfunction(s) in the serotonergic transmitter system, such as low baseline serotonin levels, remains to be established

SPECT and PET in Eating Disorders

Medical imaging techniques like PET and SPECT have been applied for investigation of brain function in anorexia and bulimia nervosa. Regional abnormalities have been detected in cerebral blood flow, glucose metabolism, the availability of several neurotransmitter receptors (serotonin 1A and 2A, dopamine D2/D3, histamine H1, mu-opioid, GABA(A)-benzodiazepine, and cannabinoid CB1), stimulant-induced dopamine release, presynaptic FDOPA influx, and the density of serotonin transporters. Different subtypes of eating disorders appear to be associated with specific functional changes. It is hard to judge whether such changes are a consequence of chronic dietary restrictions or are caused by a putative anorexia (or bulimia) nervosa endophenotype. Many abnormalities (particularly those of glucose metabolism) appear to be reversible after restoration of weight or normal patterns of food intake and may represent consequences of purging or starvation. However, some changes of regional flow and neurotransmitter systems persist even after successful therapy which suggests that these reflect traits that are independent of the state of the illness. Changes of the serotonergic system (altered activity of 5-HT1A and 5-HT2A receptors and 5-HT transporters) may contribute to dysregulation of appetite, mood, and impulse control in eating disorders and may represent a trait which predisposes to the development of anxiety, obsessionality, and behavioral inhibition. Assessment of functional changes in the brain with PET or SPECT may have prognostic value and predict neuropsychological status after several years of therapy

The Center for Integrated Molecular Brain Imaging (Cimbi) database

AbstractWe here describe a multimodality neuroimaging containing data from healthy volunteers and patients, acquired within the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) in Copenhagen, Denmark. The data is of particular relevance for neurobiological research questions related to the serotonergic transmitter system with its normative data on the serotonergic subtype receptors 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 and the 5-HT transporter (5-HTT), but can easily serve other purposes.The Cimbi database and Cimbi biobank were formally established in 2008 with the purpose to store the wealth of Cimbi-acquired data in a highly structured and standardized manner in accordance with the regulations issued by the Danish Data Protection Agency as well as to provide a quality-controlled resource for future hypothesis-generating and hypothesis-driven studies.The Cimbi database currently comprises a total of 1100 PET and 1000 structural and functional MRI scans and it holds a multitude of additional data, such as genetic and biochemical data, and scores from 17 self-reported questionnaires and from 11 neuropsychological paper/computer tests. The database associated Cimbi biobank currently contains blood and in some instances saliva samples from about 500 healthy volunteers and 300 patients with e.g., major depression, dementia, substance abuse, obesity, and impulsive aggression. Data continue to be added to the Cimbi database and biobank

Neuroticism Associates with Cerebral in Vivo Serotonin Transporter Binding Differently in Males and Females

Background: Neuroticism is a major risk factor for affective disorders. This personality trait has been hypothesized to associate with synaptic availability of the serotonin transporter, which critically controls serotonergic tone in the brain. However, earlier studies linking neuroticism and serotonin transporter have failed to produce converging findings. Because sex affects both the serotonergic system and the risk that neuroticism poses to the individual, sex may modify the association between neuroticism and serotonin transporter, but this question has not been investigated by previous studies. Methods: Here, we combined data from 4 different positron emission tomography imaging centers to address whether neuroticism is related to serotonin transporter binding in vivo. The data set included serotonin transporter binding potential values from the thalamus and striatum and personality scores from 91 healthy males and 56 healthy females. We specifically tested if the association between neuroticism and serotonin transporter is different in females and males. Results: We found that neuroticism and thalamic serotonin transporter binding potentials were associated in both males and females, but with opposite directionality. Higher neuroticism associated with higher serotonin transporter binding potential in males (standardized beta 0.292, P = .008), whereas in females, higher neuroticism associated with lower serotonin transporter binding potential (standardized beta -0.288, P = .014). Conclusions: The finding is in agreement with recent studies showing that the serotonergic system is involved in affective disorders differently in males and females and suggests that contribution of thalamic serotonin transporter to the risk of affective disorders depends on sex.Peer reviewe

Serotonergic Dysfunction in Parkinson's Disease and Its Relevance to Disability

Growing evidence suggests that Parkinson's disease is not solely affecting the dopaminergic system. Results from biochemical, animal, postmortem, and functional imaging studies have revealed that other neurotransmitter systems are affected as well, including the serotonergic system. With the use of in vivo positron emission tomography functional imaging, it has been shown that serotonergic terminals are affected at a varying, nonlinear degree starting early in the clinical course of Parkinson's disease. Tremor and the majority of nonmotor symptoms do not seem to respond adequately to dopaminergic medication. Recent studies suggest that serotonergic dysfunction has a direct relevance to Parkinson's disease symptoms, the so-called nonmotor symptoms, including depression, fatigue, weight changes, and visual hallucinations. These in vivo findings indicate that agents acting on the serotonergic system could help towards alleviating these symptoms. This paper aims to review the current literature and to highlight the need for further in vivo investigations

The expression of platelet serotonin transporter (SERT) in human obesity

Serotonin (5-HT) is a well-known modulator of eating behavior. However, the molecular mechanisms linking its action to body weight balance have been only partially elucidated. Since platelets are a suitable peripheral model to study 5-HT transport, metabolism and release, we herein evaluated the expression of the platelet 5-HT re-uptake system (SERT) by [3H]-paroxetine binding assay. A cohort of 114 unrelated individuals (34 males, 80 females; age, mean +/- SD: 38.57 +/- 12.47 years) without major psychiatric disorders, was recruited following a naturalistic design regarding age or gender and classified accordingly to their body mass index (BMI). Subjects were divided into 5 groups: normal-weight (NW), overweight (OW) and grade I-III obese (OB) individuals. For gender analyses, data were transformed into [3H]-paroxetine density (Bmax)/BMI ratios to overcome both the disparity of women vs. men number and anthropometric differences between sexes.[3H]-paroxetine Bmax (SERT density, fmol/mg proteins) was reduced in platelet membranes of grade II (p < 0.01) and III (p < 0.001) obese subjects vs. controls and in overweight subjects (p < 0.05) vs. grade III obese individuals. Considering all patients together, a strong negative correlation between Bmax and BMI (r = -0.449; P < 0.0001) was demonstrated. Conversely, [3H]-paroxetine KD (dissociation constant, nM) did not differ among groups. No gender-related variation concerning Bmax/BMI ratios was observed in this cohort of subjects.The down-regulation of SERT in platelet membranes of severe human obesity (BMI > 35 Kg/m2) confirms the involvement of 5-HT system in body weight gain. Moreover, this findings may help to elucidate those monoamine-endocrine networks acting on fat storage, adipocyte signaling and energy balance. Targeting 5-HT/5-HT-related markers will possibly uncover the existence of human obesity subtypes

Neuroendocrine stress responsiveness in human obesity and non-obesity controls

BACKGROUND: Obesity is a leading health burden of the 21st century. Alterations of the individual endocrine stress response and the monoamine system may pathophysiologically contribute to the obesity pandemic and its metabolic and mental complications. OBJECTIVES: (i) to measure hypothalamic-pituitary-adrenal (HPA) axis responsiveness and its relation to serum concentrations of the arginine-vasopressin (AVP) surrogate copeptin in subjects with obesity (OB) compared to non-obesity controls (NOC), (ii) to test whether HPA axis responsiveness and copeptin are related to central noradrenaline (NA) transporter (NAT) availability, (iii) to assess brain serotonin transporter (SERT) binding potentials in OB compared to NOC. METHODS: 40 subjects with obesity (BMI > 35kg/m2) were compared to 25 non-obesity controls, matched for age and sex. (i) All individuals underwent the combined dexamethasone/corticotropin releasing hormone (dex/CRH) test. Plasma ACTH and cortisol curve parameters were derived, and copeptin was assessed in the 1500h sample. (ii) Positron emission tomography (PET) was applied in 10 OB and 10 NOC using the NAT-selective radiotracer S,S-[11C]O-methylreboxetine (MRB) and associated to curve indicators derived from the dex/CRH test as well as to copeptin. (iii) PET using the SERT selective radiotracer [11C] DASB was performed in 30 OB and 15 NOC for intergroup comparison. RESULTS: (i) OB subjects showed an increased HPA axis responsiveness as measured by cortisol concentrations after CRH stimulation. Correspondingly, the AVP surrogate copeptin was higher in OB along with being significantly associated to HPA axis reactivity. OB subjects had a higher adrenal sensitivity as measured by a lower ACTH/cortisol ratio. (ii) In NOC, the HPA response was related to NAT availability of the amygdala and the orbitofrontal cortex while in OB, this association was located in the hypothalamus. (iii) There were no differences in SERT availability between OB and NOC, but a higher inter-regional SERT connectivity was observed in OB. CONCLUSION: This work supports the notion of an increased endocrine stress response in human obesity, pointing to interacting alterations of the HPA and neurohypophyseal axes. Normally, these stress axes seem to be linked to prefrontal-limbic NA signaling, whereas a loss of this association in favor of a hypothalamic-centered relation is observed in OB. The SERT network pattern is more closely inter-related in OB, albeit central SERT concentrations per se do not differ between OB and NOC.:ABBREVIATIONS 4 LIST OF FIGURES 5 I. BIBLIOGRAPHIC DESCRIPTION 6 II. INTRODUCTION 7 2.1 Obesity as a global health burden 7 2.2 Neurobiology of stress 8 2.3 Stress and obesity 8 2.4 Neuroendocrine correlates of the stress response – The hypothalamic pituitary-adrenaland neurohypophyseal axes 9 2.4.1 Anatomy of the hypothalamic-pituitary-adrenal and neurohypophyseal axes 10 2.4.2 The role of CRH, ACTH and cortisol in the context of metabolism and obesity 11 2.4.3 The role of AVP in the context of metabolism and obesity 12 2.4.4 Measuring HPA axis responsiveness by means of the combined dexamethasonecorticotropin-releasing hormone (dex/CRH) test 12 2.4.5 Measuring AVP secretion by its equally-released surrogate copeptin 14 2.5 The noradrenergic system in the context of obesity and stress axis modulation 14 2.5.1 NA and its influence on feeding behavior16 2.5.2 The association of the noradrenergic system with the HPA and neurohypophyseal axes 16 2.5.3 Monoamine transporters as regulators of neurotransmitter signaling 17 2.5.4 Noradrenaline transporter imaging 18 2.6 The serotonergic system in obesity 19 2.6.1 Role of serotonin in the context of feeding behavior and metabolism 20 2.6.3 5-HTT imaging 21 2.7 Objectives and hypotheses 22 2.8 Study design 23 III. RESULTS 24 3. 1 Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity 24 3. 2 Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls 34 3. 3 Central serotonin transporter availability in highly obese individuals compared with nonobese controls: A [11C] DASB positron emission tomography study 46 IV. SUMMARY 56 4.1 Subjects with obesity show an enhanced HPA axis responsiveness which correlates to serum concentrations of the AVP surrogate copeptin and abdominal fat distribution 56 4.2 HPA axis responsiveness and copeptin concentrations are differentially related to central NAT availability in subjects with obesity compared to non-obesity controls 58 4.3 Central serotonin transporter availability does not significantly differ in subjects with obesity compared to their non-obesity counterparts 59 4.4 Future direction 61 V. References 62 VI. APPENDICES 79 6.1 Curriculum vitae 79 6.2 Publications 81 6.3 Scientific contribution of the doctoral candidate to the publications 82 6.4 Declaration of the independent writing of this thesis 83 6.5 Acknowledgements 8

Clinical and PET Imaging Studies in Parkinson’s Disease Motor and Non-Motor Complications: Serotonergic and Dopamimergic Mechanisms and Applications in Treatment

The clinical course of Parkinson’s disease (PD) is complicated by the development of motor and non-motor complications. This thesis, using clinical motor and non-motor assessments and positron emission tomography (PET) imaging with 11C-raclopride, 11CDASB and 18F-DOPA, aims to explore in PD the role of: (1) postsynaptic dopamine D2 receptor dysfunction, (2) serotonergic dysfunction in the development of non-motor symptoms such as depression and body weight change, (3) striatal serotonergic neurons in levodopa- and graft -induced dyskinesias (LIDs and GIDs), and (4) the efficacy of treatment with continuous dopaminergic stimulation. The main findings are as follows: (1) D2 receptor dysfunction in the hypothalamus but not in the putamen was evident in PD, possibly accounting for the development of non-motor symptoms. (2) A staging of serotonergic dysfunction throughout the clinical course of PD has been demonstrated in this thesis and showed that serotonergic system is involved early on. (3) Higher serotonin transporter availability has been found in PD patients with elevated depressive symptoms and in PD patients with significant changes in their body weight. (4) Striatal serotonergic terminals are involved in peak-dose LIDs in PD, and administration of a high bolus dose of a 5-HT1A agonist was able to normalize extracellular dopamine levels and alleviate dyskinesias. (5) Excessive serotonergic innervation was found in two PD patients with GIDs who had experienced major recovery after striatal transplantation with fetal cells. GIDs were markedly attenuated by repeated administration of low doses of a 5-HT1A agonist, which dampens transmitter release from serotonergic neurons, indicating that serotonergic hyperinnervation was the likely cause of GIDs. (6) Continuous dopaminergic stimulation with levodopa intestinal gel induced good clinical response and stable and prolonged synaptic levels of striatal dopamine release. My observations provide fundamental insight for the role and interaction of serotonergic and dopaminergic systems in the pathophysiology of PD and have key implications for the management of motor and non-motor complications with drugs or cell therapies

Dopamine, opioid and serotonin neurotransmission in behavioral addictions

Behavioral addictions are psychiatric disorders, in which the object of addiction is not a drug but instead behavior itself, such as gambling or eating. Behavioral addictions share clinical features with substance use disorder, including tolerance against behavior, continued behavior despite negative consequences, withdrawal symptoms and craving. However, little is known about the pathophysiology of these disorders. Behavioral addictions may also serve as a model to investigate the brain reward system at its purest form, without confounding chemical properties of misused drugs. The aim of this study was to investigate brain neurotransmitter function in behavioral addictions. Brain dopamine, opioid and serotonin systems were investigated in pathological gambling (PG), in binge eating disorder (BED) and in a control group using positron emission tomography (PET). PET scans were performed using [18F]fluorodopa to target presynaptic dopamine synthesis rate; [11C]carfentanil to label μ-opioid receptors (MORs); and [11C]MADAM to label serotonin transporter. Statistical analyses covered betweengroup comparisons in all three groups, intraregional PET tracer correlations in the PG and the control groups, and correlations between impulsivity and tracer binding in the PG and the control groups. BED patients showed decreased nucleus accumbens dopamine synthesis, wide-spread decreases in MOR binding, and regionally selective increases and decreases in SERT binding, whereas PG patients failed to show any changes in relation to controls. The changes were independent from possible confounding factors. Dopamine synthesis rate correlated positively with MOR binding in the basal ganglia in both PG and control groups. Impulsivity correlated inversely with SERT binding in the prefrontal cortex in controls. This association was lost in PG, and instead, midbrain MOR binding was related both with impulsivity and nucleus accumbens dopamine synthesis rate. The results of this study indicate that phenotypically distinct behavioral addictions differ also by their neurobiology. Importantly, the findings contrast with previously published results in substance addictions, indicating individual neurobiology in distinct addiction disorders. Whether the observed neurotransmitter alterations in BED and altered relationship between receptor densities and impulsivity in PG reflect predisposing pathophysiology or a neural adaptation remains to be established.Aivojen dopamiini-, opioidi- ja serotoniinitoiminta toiminnallisissa riippuvuuksissa Toiminnalliset riippuvuudet ovat psykiatrisia sairauksia, joissa riippuvuuden kohde ei ole kemiallinen aine vaan toiminta tai käytösmalli, kuten esimerkiksi rahapelaaminen tai syöminen. Toiminnallisilla riippuvuuksilla ja päihderiippuvuuksilla on paljon yhteisiä piirteitä, mukaan lukien sietokyvyn nousu, riippuvuuden kohteena olevan toiminnan jatkaminen huolimatta epäedullisista seurauksista, vieroitusoireet ja himo. Kuitenkaan toiminnallisten riippuvuuksien patofysiologiaa ei juurikaan tunneta. Toiminnallisia riippuvuuksia voidaan käyttää myös mallina tutkittaessa aivojen palkkiojärjestelmää puhtaimmillaan ilman päihteiden aiheuttamaa kemiallista sekoittavaa vaikutusta. Tämän tutkimuksen tarkoituksena oli tarkastella aivojen välittäjäaineiden toimintaa toiminnallisissa riippuvuuksissa. Aivojen dopamiini-, opioidi- ja serotoniinijärjestelmiä tutkittiin peliriippuvuudessa, ahmintahäiriössä ja kontrolliryhmässä positroniemissiotomografialla (PET). PET-kuvauksissa [18F]fluorodopa kuvasi presynaptista dopamiinin tuotantokykyä, [11C]karfentaniili sitoutui μ-opioidireseptoriin (MOR) ja [11C]MADAM puolestaan sitoutui serotoniinin takaisinottajaan (SERT). Tilastollisessa analyysissa tarkasteltiin kaikkien ryhmien välisiä eroja merkkiaineiden sitoutumisessa. Lisäksi peliriippuvuudessa ja kontrolliryhmässä tarkasteltiin eri merkkiaineiden sitoutumisen välisiä riippuvuussuhteita ja impulsiivisuuden ja merkkiaineiden sitoutumisen riippuvuussuhteita. Ahmintahäiriössä dopamiinin tuotantokyky oli alentunut accumbens-tumakkeessa, MOR-sitoutuminen oli alentunut laaja-alaisesti aivojen eri osissa ja SERT-sitoutumisessa nähtiin alueellisesti vaihtelevia sitoutumisen nousuja ja laskuja, kun taas peliriippuvuus ei eronnut kontrolleista minkään merkkiaineen osalta. Muutokset eivät johtuneet mahdollisista sekoittavista tekijöistä. Dopamiinin tuotantokyky korreloi tyvitumakkeiden MORsitoutumisen kanssa sekä peliriippuvuudessa että kontrolleilla. Impulsiivisuus korreloi otsalohkon SERT-sitoutumisen kanssa kontrolliryhmässä, mutta tämä riippuvuussuhde ei ilmennyt peliriippuvuudessa, jossa sen sijaan keskiaivojen MOR-sitoutuminen korreloi sekä impulsiivisuuden että accumbens-tumakkeen dopamiinin tuotantokyvyn kanssa. Tämän tutkimuksen tulokset osoittavat, että ilmiasultaan erilaiset toiminnalliset riippuvuudet eroavat myös neurobiologisesti toisistaan. Lisäksi tulokset poikkeavat aiemmin julkaistuista tuloksista päihderiippuvuuksissa, mikä tarkoittaa yksilöllisen neurobiologisen taustan ilmenemistä eri riippuvuussairauksissa. Edelleen jää selvitettäväksi, heijastavatko hermovälittäjäaineiden muutokset ahmintahäiriössä sekä hermovälittäjäaineiden ja impulsiivisuuden riippuvuussuhteiden muutokset peliriippuvuudessa altistavaa patofysiologiaa vai hermostollista mukautumista