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Title: The cerebral type 1 cannabinoid receptor as modulator in dopaminergic transmission disorders: addiction and psychosis
Other Titles: De cerebrale type 1 cannabinoid receptor als modulator bij stoornissen in de dopaminerge neurotransmissie: verslaving en psychose
Authors: Ceccarini, Jenny
Issue Date: 17-Dec-2012
Description: SUMMARY :
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.
Table of Contents: 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 267
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Nuclear Medicine & Molecular Imaging
Radiopharmaceutical Research
Research Group Psychiatry

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