Behavioral Neurobiology of the Endocannabinoid System (eBook)

Behavioral Neurobiology of the Endocannabinoid System 3
Preface 5
Contents 6
Biochemistry, Pharmacology, Genetics & Chemistry
The Life Cycle of the Endocannabinoids: Formation and Inactivation 13
Cannabinoid Signalling in the CNS 15
What Are Endocannabinoids? 15
Ester Endocannabinoids 16
Synthesis of Ester Endocannabinoids 16
Regulation of Phospholipase C Activity 19
Regulation of DGL Activity 19
Alternative Pathways of DAG and 2AG Synthesis 20
Hydrolysis of Ester Endocannabinoids 22
Amide Endocannabinoids 24
Synthesis of NAPEs 24
Synthesis of Amide Endocannabinoids 25
Pharmacological and Biochemical Manipulation of NAPE-PLD Activity 26
Alternative Pathways of Amide ECB Generation 28
Hydrolysis of Amide Endocannabinoids 30
FAAH1 Activity 30
FAAH2 Activity 31
NAAA Activity 32
Other Routes of ECB Transformation 32
Oxidative Metabolism of ECBs 33
Cyclooxygenase Activity 33
Lipoxygenase Activity 34
Cytochrome P450s and Epoxygenase Activity 34
Stimulation of ECB Synthesis and Release 35
Conclusion 37
References 37
Endocannabinoid Receptor Pharmacology 46
GPCR Overview 47
Receptor Pharmacology 48
GPCR Signaling 48
Radioligand Binding 49
GTPgammaS Binding as a Measure of GPCR Function 50
CB1 Receptor Gene Structure 53
Chromosomal Structure, Potential Alternative Splicing 53
CNR1 Polymorphisms 53
CB2 Receptor Gene Structure 54
CB2 Receptor Chromosomal Localization and Potential Alternative Splicing 54
CNR2 Polymorphisms 55
Structural Characteristics of the CB1 Receptor 55
Structural Characteristics of the CB2 Receptor 57
CB1 and CB2 Receptor Localization 58
Cellular Signaling of CB1 and CB2 Receptors 58
Inhibition of Adenylyl Cyclase - Gi/o Coupling of CB1 and CB2 Receptors 58
Cannabinoid Receptor Activation of MAP Kinases 59
Crosstalk Between Cannabinoid and Other Receptors 59
Transactivation Between Cannabinoid Receptors and Tyrosine Kinase Receptors 59
Cannabinoid Receptor-Mediated Modulation of Ion Channels 60
Implications of Constitutive Receptor Activity, Protean Agonism, and Inverse Agonism 60
Cannabinoid Receptor Ligands 62
Non-Selective CB1/CB2 Receptor Agonists 62
CB1 Receptor Antagonists 64
CB2 Receptor Agonists 64
CB2 Receptor Antagonists 65
Allosteric Modulators of Cannabinoid Receptors 65
Non-CB1/Non-CB2 Receptors 66
GPR55 66
Interactions of Cannabinoids with Ion Channels 66
Conclusions 67
References 67
Endocannabinoid Receptors: CNS Localization of the CB1 Cannabinoid Receptor 73
Introduction 74
Methodological Considerations for Localization Studies on the Endocannabinoid System 76
Negative Controls for Positive Findings 76
Positive Controls for Negative Findings 77
Quantification of Positive Findings 78
Regional Distribution 78
Cellular Distribution 82
Subcellular Distribution 84
Distribution of Other Molecular Components Involved in 2-AG Signaling 87
Conclusions 88
References 90
Pharmacological Tools in Endocannabinoid Neurobiology 95
Cannabinoid Receptor Ligands 96
Natural Products and Non-Selective Ligands 97
Classical Cannabinoids 98
Non-Classical Cannabinoids 98
Aminoalkylindoles 99
Eicosanoids 99
CB1-Selective Ligands 100
Agonists 100
Antagonists and Inverse Agonists 100
Allosteric Modulators 102
CB2-Selective Ligands 103
Agonists 103
Antagonists 104
Ligands of Other ECB Receptors 105
Modulators of ECB Metabolism 106
ECB Catabolism 106
Inhibition of Anandamide Transport 107
FAAH Inhibitors 108
MGL Inhibitors 110
NAAA Inhibitors 111
ECB Synthesis 112
References 113
Genetic Models of the Endocannabinoid System 119
Introduction 120
Genetic Models 122
Available Tools 122
Null Mutant Mouse Lines 128
Conditional CB1 Receptor Mutants 132
Complications with Cre Recombinase-Expressing Lines 136
Methodological Considerations on Behavioural Experiments with Mutant Mice 137
Caveats in Genetics and Pharmacology 139
Perspectives 141
References 141
Endocannabinoid Signaling in Neural Plasticity 148
Introduction 149
Definitions, Scope, Limitations, and Caveats 149
ECBs: Basic Principles 150
ECBs Regulate Synaptic Plasticity 151
Short-Term Plasticity 151
Short-Term Target-Dependent Plasticity 153
Long-Term Plasticity 153
Striatum 154
Nucleus Accumbens (NAc) 155
Hippocampus 155
Cerebellum 156
Amygdala 157
Ventral Tegmental Area (VTA) 157
Cortex 157
Mechanisms of ECB-Dependent Long-Term Plasticity 158
Sufficiency of CB1R Activation for ECB-LTD(or -iLTD) Induction 158
Molecular Mechanisms of ECB-LTD (or iLTD) Maintenance 160
Spike-Timing Dependent Plasticity (STDP) 162
Interneurons Mobilize ECBs 164
Plasticity of the ECB System 165
Use-Dependence of CB1R Efficacy 165
Tonic CB1R Activation and ECB Regulation 166
Plasticity of ECB Mobilization 169
ECB Transport as a Synaptically Modifiable Process 170
The ECB System and Seizures 171
Interactions Between AEA and 2-AG 172
Conclusion 173
References 174
Lessons from Nonmammalian Species 180
Invertebrates 181
Insects 181
Ants 181
Aquatic Invertebrates and Annelids 183
Hydra (Hydra Vulgaris) 183
Planaria 184
Leech 186
Snail 188
Sea Urchin 188
Urochordates Including the Sea Squirt (Ciona intestinalis) 189
Nonmammalian Vertebrates 191
Fish 191
Amphibians 193
Birds 196
Lessons Learned 200
References 202
Physiology and Pathophysiology 206
Roles of the Endocannabinoid System in Learning and Memory 207
Introduction 208
Expression of Cannabinoid Receptors in the Brain: Focus on CB1 209
The ECS and Learning and Memory 210
Pharmacology of Exogenous Cannabinoid Agonists and Physiology of the ECS: Important Differences in Complex Functions 211
Involvement of the Endocannabinoid System in Learning and Memory 214
The ECS and Working Memory 214
The ECS and Long-Term Memories 216
The ECS and ``Declarative´´-Type Memories 216
The ECS and Recognition Memory 216
The ECS and Spatial Memory 217
The ECS and Procedural Memory 218
The ECS and Operant Conditioning 218
The ECS and Habits 219
The ECS and Procedural Strategies in a Spatial Task 220
The ECS and Emotional Memory 220
The ECS and Aversive Memory 220
The ECS and Fear Memory 221
Acquisition of Fear Memories 222
Consolidation, Re-consolidation and Extinction of Fear Memories 222
Intracellular Cascades 223
A Possible Mechanism for ECS-Dependent Extinction of Fear Memories in the Amygdala 224
General Conclusions 230
References 231
Endocannabinoids and the Non-Homeostatic Control of Appetite 237
Obesity and the Problem of Homeostasis 238
Eating for Survival 240
Gluttony and Externality 242
Endocannabinoids in Food Craving, Anticipation and Palatability 244
THC Hyperphagia 244
Orexigenic Actions of the Endocannabinoids 245
Behavioural Characterization of Cannabinoid Hyperphagia: The Reward Hypothesis 246
Endocannabinoids and ``Wanting´´: Primary Motivational Actions 248
Endocannabinoids and ``Liking´´: Secondary Motivational Actions 251
Endocannabinoid-Opioid Interactions in Eating Motivation 252
Endocannabinoids and Interactions with Other Orexigens 253
Conclusion 254
References 255
Cannabinoid/Endocannabinoid Signaling Impact on Early Pregnancy Events 260
Introduction 261
Endocannabinoid Systems 261
AEA Synthesis and Degradation 262
2AG Synthesis and Degradation 263
Cannabinoid Receptors 264
Peri-implantation Events 265
Preimplantation Embryo Development 266
Oviductal-Uterine Embryo Transport 268
Implantation 271
Conclusion 273
References 274
Targeting the Cannabinoid System to Produce Analgesia 279
Introduction 280
The Endogenous Cannabinoid System 281
Endocannabinoids 282
Endocannabinoid Synthesis 282
Endocannabinoid Metabolism 282
Endocannabinoids and Pain Processing 282
CB Receptor-Mediated Analgesia 283
Attenuation of Endocannabinoid Catabolism Produces Analgesia 284
Arthritis - A Therapeutic Target for Cannabinoids? 285
References 287
Integration of Endocannabinoid Signaling into the Neural Network Regulating Stress-Induced Activation of the Hypothal 292
Stress and the Hypothalamic-Pituitary-Adrenal Axis 293
The Endocannabinoid System 295
Endocannabinoid-Mediated Regulation of the HPA Axis 296
Endocannabinoid Signaling within the HPA Axis 296
Endocannabinoid Signaling Inhibits HPA Axis Activity 297
At What Sites of Action Does Endocannabinoid Signaling Modulate HPA Axis Activity? 298
Acute Stress-Induced Modulation of Endocannabinoid Signaling: Contributions to Glucocorticoid Negative Feedback 300
Chronic Stress-Induced Regulation of Endocannabinoid Signaling: A Driving Force for Stress Habituation 303
Conclusion 304
References 305
Pathology 310
Drug Addiction 311
Introduction 312
Drug Addiction 312
Endocannabinoid System in Brain Reward Circuitry 313
Release of Endocannabinoids by Abused Drugs 314
Endocannabinoids in Drug-Seeking and Relapse 315
Cannabinoids 316
Self-Administration of Cannabinoids 317
Drug Self-Administration Paradigm 317
Fixed-Ratio Schedule 318
Second-Order Schedule and Drug Seeking 322
Conditioned Place Preference and Aversion with Cannabinoids 324
THC and Synthetic Cannabinoids 324
AEA 325
Discriminative-Stimulus Effects of Cannabinoids 325
Tolerance, Physical Dependence and Behavioral Sensitization 327
Tolerance 327
Physical Dependence 328
Behavioral Sensitization 329
Opioids 330
Alcohol 331
Nicotine 332
Psychostimulants 333
Cocaine and Methylphenidate 334
Cocaine 334
Methylphenidate 335
Amphetamine, Methamphetamine and 3,4-Methylendioxymethamphetamine (MDMA) 335
Endocannabinoid System and Treatment of Drug Addiction 336
References 337
Role of Endocannabinoid Signaling in Anxiety and Depression 349
Human Studies Suggesting a Role for Endocannabinoid Signaling in Anxiety 350
Animal Studies Indicating a Role for ECS in Anxiety 351
Effects of CB1 Receptor Blockade and Genetic Deletion on Unconditioned Anxiety Behaviors 351
Effects of Pharmacological and Genetic Augmentation of ECS on Unconditioned Anxiety Behaviors 353
Effects of CB1 Receptor Deletion and Pharmacological Blockade on Conditioned Anxiety Behaviors 354
Effects of ECS Augmentation on Conditioned Anxiety Behaviors 355
Neural Mechanisms Underlying Endocannabinoid Modulation of Anxiety 356
Human Studies Suggesting a Role for ECS in Depression 359
Cannabis Use and Depression 359
Depression and the ECS 360
Animal Studies Suggesting a Role for ECS in Depression 361
Evidence That Alteration of CB1 Receptor Signaling Results in Anti-Depressant-Like Effects 361
Evidence That Environmental Contexts That Produce Depression-Like Symptoms Alter ECS 363
Evidence That Anti-Depressant Therapies Alter ECS 364
Neural Mechanisms Underlying Endocannabinoid Modulation of Depression 364
Clinical Implications for Endocannabinoid-Based Therapeutics for Anxiety and Depressive Disorders 366
References 367
Feeding Disorders and Obesity 374
Introduction 375
Historical Background 376
Modes of Action by which Endocannabinoids Promote Energy Storage 376
Endocannabinoids Promote Energy Storage in the Brain 376
Endocannabinoids Promote Energy Storage at a Peripheral Level 377
Adipose Tissue 377
Liver 378
Skeletal Muscle 378
Endocrine Pancreas 378
Obesity as a Disease Model of Endocannabinoid Overactivation 379
Endocannabinoids and Central Eating Disorders 380
How CB1 Receptor Antagonism May Act Against Obesity and Metabolic Complications 380
Pharmacological Implications in Humans 382
Rimonabant 382
Taranabant 383
Conclusions 383
References 384
Schizophrenia 387
Introduction 388
Neurobiology of the Endocannabinoid System in Schizophrenia 389
Animal Studies 389
Human Post-Mortem Studies 390
Clinical Studies 391
Cannabis Administration 392
Conclusions and Model 393
References 395
Tourette´s Syndrome 397
Tourette´s Syndrome 398
The Clinical Picture of Tourette´s Syndrome 398
The Aetiology of Tourette´s Syndrome 399
Treatment of Tourette´s Syndrome 399
Future Perspectives in the Treatment of Tourette´s Syndrome 400
Treatment of Tourette´s Syndrome with Cannabinoids 400
Anecdotal Reports 400
Uncontrolled Single Case Studies 401
Controlled Single-Dose Trial 402
Six-Week Randomized Trial 403
Adverse Effects 404
Central Cannabinoid Receptor (CNR1) Gene in Tourette´s Syndrome 405
In Vivo Imaging of Central Cannabinoid CB1 Receptors in TS Using [123I]AM281 and SPECT 405
Possible Explanations for Beneficial Effects of Cannabinoids in TS 405
Conclusions and Perspective 407
References 408
Index 411