August 21, 2018

status: publishe

The cerebral type 1 cannabinoid receptor as modulator in dopaminergic transmission disorders: addiction and psychosis

Table of contents Acknowledgment V Table of contents XI List of abbreviations XIII Introduction and Objectives of the Thesis 1 CHAPTER I: Introduction 3 1.1 Drug addiction 3 1.2 Psychosis 9 1.3 The Endocannabinoid System (ECS) 10 1.4 Cannabinoid-Dopamine interaction in the mesocorticolimbic pathway 12 1.5 Involvement of the ECS in Drug Addiction and Psychosis 14 1.6 Positron Emission Tomography 17 1.7 PET imaging of the brain Cannabinoid CB1 Receptor 20 1.8 PET imaging of the Dopaminergic System 22 1.9 Objectives and Overview of the Thesis 25 PART 1: CB1R Availability in Alcohol and Cannabis Addiction 27 CHAPTER II: Changes in cerebral CB1R Receptor Availability after Acute and Chronic Alcohol Abuse and Monitored Abstinence 29 CHAPTER III: Transient Changes in the Endocannabinoid System after Acute and Chronic Ethanol Exposure in the rat: a combined PET and Microdialysis 57 CHAPTER IV: Decreased Cannabinoid CB1 Receptor Availability in Chronic Cannabis Users and Association with Personality Traits 79 PART 2: CB1R Availability in Psychosis 103 CHAPTER V: Increased Ventral Striatal CB1 Receptor Availability is Related to Negative Symptoms in Schizophrenia 105 PART 3: in vivo Dopamine Release Detection 129 CHAPTER VI: Optimization of in vivo Dopamine Release Detection using [18F]fallypride PET 131 CHAPTER VII: Psychosocial Stress is Associated with in vivo Dopamine Release in Human Ventromedial Prefrontal Cortex: a Positron Emission Tomography study using [18F]fallypride 155 CHAPTER VIII: Delta-9-Tetrahydrocannabinol-Induced Dopamine Release as a Function of Psychosis Risk: 18F-fallypride Positron Emission Tomography study 177 PART 4: CB1R-Dopamine Release Interactions 195 CHAPTER IX: Cannabinoid Receptor Availability Regionally Modulates the Magnitude of Dopamine Release in vivo 197 CHAPTER X: Hippocampal Dopamine Release in Psychosis is Modulated by CB1R Availability: a combined [18F]MK-9470 and [18F]fallypride PET study 215 General Discussion and Conclusion 231 CHAPTER XI: General Discussion and Conclusion 233 11.1 Main Contributions 233 11.2 Cerebral CB1R Availability in Alcohol and Cannabis Addiction 234 11.3 Cerebral CB1R Availability in Schizophrenia 236 11.4 Potential Therapeutic Implications 239 11.5 Development, Application and Optimization of a Method for in vivo Dopamine Release Detection 242 11.6 Interaction between CB1R Availability and Dopamine Release 244 11.7 Methodological Considerations 247 11.8 Future Perspectives 249 Summary 251 Samenvatting 255 Curriculum Vitae 259 List of Publications 261 Reference List 267SUMMARY : The endocannabinoid system (ECS) is a widespread neuromodulatory system in the brain. The ECS consists mainly of cannabinoid receptors, their endogenous ligands (endocannabinoids) of which anandamide and 2-arachidonoylglycerol (2-AG) are the best characterized examples, and transport and degradation proteins. Endocannabinoids are lipids synthesized and released ‘on-demand’ in dendrites subjected to membrane depolarization. In contrast to classic neurotransmitters, endocannabinoids are not stored in vesicles but immediately released after synthesis. They move back to the presynaptic nerve terminal where they bind to the type 1 cannabinoid receptor (CB1R) and activate it. The CB1R is predominantly presynaptically located and distributed in high concentration in the frontal neocortex, especially the anterior cingulate and orbitofrontal cortex, in the neostriatum and in the posterior cingulate and precuneus. CB1R activation modulates synaptic release of major neurotransmitter systems such as glutamate, gamma-aminobutyric acid (GABA), and indirectly also dopamine. Modulating activity of the major neurotransmitters, CB1R may interact with dopamine neurotransmission in the CNS and this has an important influence in various dopamine-related neurobiological processes (e.g. control of movement, motivation/reward) and, particularly, on different pathologies affecting these processes like drug addiction and psychosis. For decades, dopamine has been proposed as the key neurotransmitter in mediating drug reward processes and schizophrenia and related-psychoses. On the one hand, chronic drug abuse leads to a complex cascade of adaptive neurochemical alterations that induce dependence and tolerance, which is related to decreased dopaminergic function. However, the exact signaling pathways and mechanisms underlying the development of drug dependence and the propensity to relapse are still unclear, and the few available pharmacotherapeutic interventions developed for the treatment of drug dependence remain unsatisfactory. On the other hand, overactivity of mesocorticolimbic dopaminergic pathways can result in schizophrenia. Existing antipsychotics, which act mainly on dopamine and serotonin receptors, are generally not very effective in treating negative symptoms, and additionally a significant portion of patients are refractory to all current treatments. For this reason, there is still a demand for new targets with potential pharmacotherapeutic application potential. Currently, the ECS has been recognized as an important target in the common neural networks underlying addictive and psychiatric disorders. In this work, we use positron emission tomography (PET) to study in vivo human cerebral CB1R availability and dopamine release using the [18F]MK-9470 and [18F]fallypride tracers respectively. In this thesis, we first demonstrate the in vivo central key effector role of the CB1R in the common substrate of two of the most frequent forms of addiction in humans, alcohol and cannabis. Since the relevant role of the CB1R in the pharmacological actions in alcohol drinking behaviour and addiction is mainly supported by animal and pharmacological experiments, in Chapter II we investigated changes in CB1R availability after chronic alcohol abuse and monitored abstinence in alcoholic patients, and after an acute alcohol administration in healthy social drinkers. We found that, whereas acute exposure to alcohol is related to a (presumably) transient increase in CB1R availability, chronic long-term alcohol abuse leads to a significantly decreased CB1R availability that is not reversible on the short term as observed after one month of monitored abstinence. Subsequently, to further investigate and elucidate how central CB1R availability relates to endocannabinoid levels, we evaluated parallel transient changes in the levels of CB1R availability and endocannabinoid anandamide (AEA) levels in rats subjected to acute and forced chronic ethanol exposure and then abstinence, using a combined microPET and microdialysis study (Chapter III). This study provided in vivo evidence that acute ethanol consumption is associated with an enhanced endocannabinoid signaling in the nucleus accumbens, indicated by an increased CB1R availability and AEA content. In addition, chronic ethanol exposure points to regional dysfunctions in CB1R levels, incorporating hippocampus and caudate-putamen that are reversible within two weeks in this animal model. Next, in Chapter IV, we demonstrated that also chronic cannabis use downregulates CB1R availability in mainly neocortical regions and this interacts with personality traits involved in addictive behaviour. Secondly, we investigated in vivo CB1R availability in an extensive sample of patients with schizophrenia (SCZ), with and without different antipsychotic treatments, and in relation to severity of psychotic symptoms (Chapter V). Compared to controls, both medicated and antipsychotic-free patients show increased CB1R availability, particularly pronounced in the nucleus accumbens, cingulate and insular cortex. Moreover the increased CB1R availability was negatively associated with negative symptoms and depression in antipsychotic-free patients, especially in the nucleus accumbens. The current in vivo data strengthens the hypothesis that the ECS is involved in the pathology of SCZ. Thirdly, as a stepping stone to study the hypothesis that CB1R expression is related to dopaminergic transmission, we developed, applied and optimized an advanced and efficient voxel-based kinetic model (the linearized simplified reference region model [LSRRM]) to detect in vivo striatal and extrastriatal dopamine release using a single [18F]fallypride imaging protocol during non-pharmacological and pharmacological activation paradigms in human subjects. Using the LSSRM, we measured for the first time in vivo extrastriatal endogenous dopamine release in healthy humans while they were performing a learning reward task and a validated stress task (Chapter VI and Chapter VII). Next, to estimate the ability of the LSRRM model to quantitate dopamine release simultaneously in both extrastriatal and striatal regions, we analyzed the kinetic characteristics of [18F]fallypride with variable dopamine stimulus intensity and task timing through simulation studies, starting from the experimental observed parameters during a monetary reward task (Chapter VI). We found that improvements in the experimental design, such as a postponement of task initiation, should increase the relative detection sensitivity of striatal dopamine release, and 120-190 min after injection are needed to evaluate both extrastriatal and striatal dopamine release. In addition, using the LSRRM method and the [18F]fallypride imaging protocol modified according to simulation studies, we wanted to test the hypothesis that Δ9-THC increases the risk of developing psychotic symptoms by stimulating striatal dopamine neurotransmission (Chapter VIII). Our results revealed significant striatal dopamine release associated with administration of Δ9-THC in both cannabis users with psychotic disorder and first-degree relatives, supporting a dopaminergic mechanism of cannabis-induced psychosis in individuals already at risk for psychosis. The last part of the work focuses on the hypothesis of CB1R as in vivo functional modulator of dopamine release capacity in healthy subjects (normodopaminergic state) after a controlled amphetamine administration paradigm (Chapter IX), and in cannabis (psychotic) users (hyperdopaminergic state) after Δ9-THC administration (Chapter X). In the last chapter, we additionally investigated whether CB1R alterations are present in cannabis users with and without psychotic illness. Although the latter results are preliminary, these data represent the first direct demonstration that CB1R is a determinant of dopamine release and they warrant further investigation in dopamine-related transmission disorders, such as addiction or psychosis. Chapter XI critically summarized the findings of this work and tried to provide a coherent interpretation of the overall work, as well as methodological evaluation and suggestions for future work. This work provides new insights on the CB1R in dopamine-related psychiatric disorders such as drug addiction and psychosis, and it may lay the basis for novel potential therapeutic strategies that directly or indirectly target the endocannabinoid pathways to modify the process of drug addiction as well as to treat psychotic symptoms.nrpages: 312status: publishe

How Acute and Chronic Alcohol Consumption Modulate Multiple Neurotransmitter Systems: A Review of Clinical PET Neuroimaging

status: Published onlin

Cannabinoid Receptor Availability Regionally Modulates the Magnitude of Dopamine Release in vivo

Status paper: FORTHCOMINGstatus: accepte

The effect of stress on delay discounting in bulimia nervosa and alcohol use disorder: a functional magnetic resonance imaging study.

Background: Stress could induce neurobiological changes in patients with bulimia nervosa (BN) and alcohol use disorder (AUD) that increase delay discounting (DD), making the short-term benefits of coping through eating or drinking outweigh long-term negative consequences. Therefore, this study explores differences in DD between patients (BN or AUD) and healthy controls (HC), the impact of stress on food and alcohol DD, and the associated changes in brain activity. Methods: A total of 102 female participants (AUD: 27, BN: 25, HC: 50; age range: 18-38 years) underwent repeated fMRI scanning while performing three DD tasks (DDT). Initially, all participants performed a monetary DDT. Then, participants performed a food or alcohol DDT before and after stress induction with the Montreal Imaging Stress Task (MIST). Specifically, patients with BN completed a food DDT,patients with AUD completed an alcohol DDT and HC were randomly allocated to either DDT. Results: No differences were found in the DD of money, food or alcohol between patients and controls before stress. However, stress increased the DD of alcohol in patients with AUD, but not in HC. Stress also increased the DD of food in HC, but not in patients with BN. Furthermore, stress caused patients with AUD to display a lower activity of the right supplementary motor area while discounting alcohol. Stress also caused HC to display a lower activity of the middle/super frontal cortex and a higher activity of the motor cortex while discounting food, but caused patients with BN to display a higher activity of the occipital cortex. Conclusion: The results suggest that stress induces neurobiological changes in patients with AUD which cause them to prefer more immediately available alcohol. However, the results observed in patients with BN suggest a more complex relation between stress and food

Transient changes in the endocannabinoid system after acute and chronic ethanol exposure and abstinence in the rat: a combined PET and microdialysis study

PURPOSE: Recent biochemical and post-mortem evidence suggests involvement of the endocannabinoid system in alcohol drinking behaviour and dependence. Using [(18)F]MK-9470 small-animal PET imaging, our primary objective was to evaluate in vivo type 1 cannabinoid receptor (CB1R) binding changes in rats subjected to several ethanol conditions: (1) at baseline, (2) after acute intraperitoneal administration of ethanol (4 g/kg) or saline, (3) after 7 days of forced chronic ethanol consumption, and (4) after abstinence for 7 and 14 days. Secondly, levels of anandamide (AEA) in the nucleus accumbens (NAcc) were investigated in the same animals using in vivo microdialysis and correlated with the changes in CB1R binding. METHODS: In total, 28 male Wistar rats were investigated. Small-animal PET was done on a FOCUS-220 tomograph with [(18)F]MK-9470. Parametric images of [(18)F]MK-9470 binding based on standard uptake values (SUV, as a measure of CB1R binding) were generated. Images were normalized to Paxinos space and analysed voxel-wise using SPM8 (p height = 0.005; k ext = 200). The AEA content was quantified using HPLC with tandem mass spectrometry detection. RESULTS: Acute ethanol administration increased relative CB1R binding in the NAcc that was positively correlated with the change in AEA levels of that region. In contrast, compared to rats at baseline, AEA levels in the NAcc were not significantly different in rats after chronic ethanol consumption or after a 14-day abstinence period. Chronic ethanol consumption decreased relative CB1R binding in the hippocampus and caudate-putamen, whereas same regions showed increased relative CB1R binding after 7 and 14 days of abstinence compared to the baseline condition. After 7 and 14 days of abstinence, relative CB1R binding additionally decreased in the orbitofrontal cortex. The magnitude of the hippocampal and frontal changes was highly correlated with daily ethanol intake. CONCLUSION: This study provides in vivo evidence that acute ethanol consumption is associated with enhanced endocannabinoid signalling in the NAcc, indicated by an increased CB1R binding and AEA content. In addition, chronic ethanol exposure leads to regional dysfunctions in CB1R levels, involving the hippocampus and caudate-putamen that are reversible within 2 weeks in this animal model.status: publishe

Simultaneous 18F-FDG PET/MR metabolic and structural changes in visual snow syndrome and diagnostic use

Abstract Purpose Visual snow syndrome (VSS) is a recently recognized chronic neurologic condition characterized by the constant perceiving of tiny flickering dots throughout the entire visual field. Metabolic overactivity and grey matter volume increase in the lingual gyrus has been reported. We investigated this by 18F-FDG PET/MR in comparison to healthy controls. Aside from voxel-based characterization, the classification accuracy of volume-of-interest (VOI)-based multimodal assessment was evaluated, also in comparison with visual analysis. Methods Simultaneous 18F-FDG PET and MR imaging was performed in 7 patients with VSS (24.6 ± 5.7 years; 5 M/2F) and 15 age-matched healthy controls (CON) (28.0 ± 5.3 years; 8 M/7F). SPM12 and voxel-based morphometric analysis was performed. A VOI-based discriminant analysis was performed with relative 18F-FDG uptake, MR grey matter (GM) volumes and their combination. A visual analysis was done by two blinded experienced readers. Results Relative increased hypermetabolism was found in VSS patients in the lingual gyrus and cuneus (p FWE < 0.05, peak change + 24%), and hypometabolism in the mesiotemporal cortex (p height,uncorr < 0.001, peak change − 14%). VSS patients also had increased GM volume in the limbic system and frontotemporal cortex bilaterally (p FWE < 0.05), and in the left secondary and associative visual cortex and in the left lingual gyrus (p height,uncorr < 0.001). Discriminant analysis resulted in 100% correct classification accuracy for 18F-FDG with lingual gyrus, cuneus and lateral occipital lobe (BA 17 and BA 18) as main discriminators. Unimodal MR- and combined 18F-FDG + MR classification resulted in an accuracy of 91% and 95%, respectively. Visual analysis of 18F-FDG was highly observer dependent. Conclusion Patients with VSS have highly significant structural and metabolic abnormalities in the visual and limbic system. VOI-based discriminant analysis of 18F-FDG PET allows reliable individual classification versus controls, whereas visual analysis of experienced observers was highly variable. Further investigation in larger series, also in comparison to VSS mimicking disorders such as migraine, is warranted. Trail registration: Retrospectively registered at clinicaltrials.gov under NCT05569733 on Oct 5, 2022

Person-specific and Pooled Prediction Models for Binge eating, Alcohol Use and Binge Drinking in Bulimia Nervosa and Alcohol Use Disorder: An Experience Sampling Method Study.

Introduction: Machine learning could play a key role in the development of new interventions for bulimia nervosa (BN) and alcohol use disorder (AUD) as it can be used to predict and identify specific triggers of binge behavior in daily life. Therefore, this study has the following two aims. First, to evaluate person-specific and pooled prediction models for binge eating (BE), alcohol use and binge drinking (BD) in daily life. Second, to identify important predictors for these behaviors. Methods: A total of 120 patients (BN: 50; AUD: 51; BN/AUD: 19) participated in an experience sampling study, where over a period of 12 months they reported on their eating and drinking behaviors as well as on several other emotional, behavioral and contextual factors in daily life. The study had a burst-measurement design, where assessments occurred 8 times a day on Thursdays, Fridays, and Saturdays in 7 bursts of 3 weeks. Afterwards, person-specific and pooled models were fit with elastic net regularized regression and evaluated with cross-validation. From these models, the variables with the 10% highest estimates were identified. Results: The person-specific models had a median AUC of 0.61, 0.80, and 0.85 for BE, alcohol use and BD respectively, while the pooled models had a median AUC of 0.70, 0.90, and 0.93. The most important predictors across the different behaviors were craving, and time of day. However, predictors concerning social context and affect differed between BE, alcohol use and BD. Conclusion: This study shows that BE, alcohol use and BD can be predicted in daily life, but that pooled models outperformed person-specific models and that models for alcohol use and BD outperformed those for BE. Future studies should investigate how model performance can be improved and how these models can be used to deliver interventions in daily life

What Has Neuroimaging Taught Us on the Neurobiology of Yoga? A Review

Yoga is becoming increasingly popular worldwide, with several implicated physical and mental benefits. Here we provide a comprehensive and critical review of the research generated from the existing neuroimaging literature in studies of yoga practitioners. We reviewed 34 international peer-reviewed neuroimaging studies of yoga using magnetic resonance imaging (MRI), positron emission tomography (PET), or single-photon emission computed tomography (SPECT): 11 morphological and 26 functional studies, including three studies that were classified as both morphological and functional. Consistent findings include increased gray matter volume in the insula and hippocampus, increased activation of prefrontal cortical regions, and functional connectivity changes mainly within the default mode network. There is quite some variability in the neuroimaging findings that partially reflects different yoga styles and approaches, as well as sample size limitations. Direct comparator groups such as physical activity are scarcely used so far. Finally, hypotheses on the underlying neurobiology derived from the imaging findings are discussed in the light of the potential beneficial effects of yoga.status: publishe

Brain PET imaging of phosphodiesterase 10A in progressive supranuclear palsy and Parkinson's disease

status: publishe