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

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

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

status: publishe

Prospective Validation of 18F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis

An objective biomarker for early identification and accurate differential diagnosis of amyotrophic lateral sclerosis (ALS) is lacking. (18)F-FDG PET brain imaging with advanced statistical analysis may provide a tool to facilitate this. The objective of this work was to validate volume-of-interest (VOI) and voxel-based (using a support vector machine [SVM] approach) (18)F-FDG PET analysis methods to differentiate ALS from controls in an independent prospective large cohort, using a priori-derived classifiers. Furthermore, the prognostic value of (18)F-FDG PET was evaluated.status: publishe

Recovery of decreased metabotropic glutamate receptor 5 availability in abstinent alcohol-dependent patients

Animal models of alcohol dependence and relapse demonstrate an important role of the glutamatergic system, in particular the cerebral metabotropic glutamate receptor 5 (mGluR5). Using [18F]FPEB positron emission tomography, it was found that chronic alcohol use leads to decreased limbic mGluR5 availability, where lower mGluR5 was associated with less craving. Here, we tested whether the state of decreased mGluR5 availability in alcohol-dependent patients normalizes during abstinence (at 2- and 6-month of detoxification) and whether initial mGluR5 imaging parameters can predict individual relapse. Methods: [18F]FPEB scans were performed in 16 recently detoxified alcohol-dependent patients (baseline condition), after 2 months (n = 10) and 6 months (n = 8) of detoxification, in comparison to 32 age- and gender-matched controls. mGluR5 availability was quantified by [18F]FPEB total distribution volume using both voxel-by-voxel and volume-of-interest analysis. During follow-up, craving was assessed using the Desire for Alcohol Questionnaire, and alcohol consumption was assessed by a Time-Line Follow Back and monitored by hair ethyl glucuronide analysis. Results: During abstinence, alcohol-dependent patients showed a sustained recovered mGluR5 availability in cortical and subcortical regions (pheight<0.001) compared to baseline, up to the levels observed in controls after 6 months in most areas except for the hippocampus, nucleus accumbens and thalamus. A higher striato-pallidal mGlu5 availability was observed at baseline in patients who relapsed during the 6-month follow-up period (+25.1%). Also, normalization of striatal mGlu5 to control levels was associated with reduced craving ("Desire and intention to drink" and "Negative reinforcement", range r = 0.72-0.94). Conclusion: Reduced cerebral mGluR5 availability in alcohol-dependent patients recovers during abstinence, and is associated with reduced craving. Higher striatal mGluR5 availability in alcohol-dependent users may be associated with long-term relapse.epub ahead of printstatus: publishe