Behavioral Neurobiology of the Endocannabinoid System

Behavioral Neurobiology of the Endocannabinoid System

Preface

Contents

Biochemistry, Pharmacology, Genetics & Chemistry

The Life Cycle of the Endocannabinoids: Formation and Inactivation

Cannabinoid Signalling in the CNS

What Are Endocannabinoids?

Ester Endocannabinoids

Synthesis of Ester Endocannabinoids

Regulation of Phospholipase C Activity

Regulation of DGL Activity

Alternative Pathways of DAG and 2AG Synthesis

Hydrolysis of Ester Endocannabinoids

Amide Endocannabinoids

Synthesis of NAPEs

Synthesis of Amide Endocannabinoids

Pharmacological and Biochemical Manipulation of NAPE-PLD Activity

Alternative Pathways of Amide ECB Generation

Hydrolysis of Amide Endocannabinoids

FAAH1 Activity

FAAH2 Activity

NAAA Activity

Other Routes of ECB Transformation

Oxidative Metabolism of ECBs

Cyclooxygenase Activity

Lipoxygenase Activity

Cytochrome P450s and Epoxygenase Activity

Stimulation of ECB Synthesis and Release

Conclusion

References

Endocannabinoid Receptor Pharmacology

GPCR Overview

Receptor Pharmacology

GPCR Signaling

Radioligand Binding

GTPgammaS Binding as a Measure of GPCR Function

CB1 Receptor Gene Structure

Chromosomal Structure, Potential Alternative Splicing

CNR1 Polymorphisms

CB2 Receptor Gene Structure

CB2 Receptor Chromosomal Localization and Potential Alternative Splicing

CNR2 Polymorphisms

Structural Characteristics of the CB1 Receptor

Structural Characteristics of the CB2 Receptor

CB1 and CB2 Receptor Localization

Cellular Signaling of CB1 and CB2 Receptors

Inhibition of Adenylyl Cyclase - Gi/o Coupling of CB1 and CB2 Receptors

Cannabinoid Receptor Activation of MAP Kinases

Crosstalk Between Cannabinoid and Other Receptors

Transactivation Between Cannabinoid Receptors and Tyrosine Kinase Receptors

Cannabinoid Receptor-Mediated Modulation of Ion Channels

Implications of Constitutive Receptor Activity, Protean Agonism, and Inverse Agonism

Cannabinoid Receptor Ligands

Non-Selective CB1/CB2 Receptor Agonists

CB1 Receptor Antagonists

CB2 Receptor Agonists

CB2 Receptor Antagonists

Allosteric Modulators of Cannabinoid Receptors

Non-CB1/Non-CB2 Receptors

GPR55

Interactions of Cannabinoids with Ion Channels

Conclusions

References

Endocannabinoid Receptors: CNS Localization of the CB1 Cannabinoid Receptor

Introduction

Methodological Considerations for Localization Studies on the Endocannabinoid System

Negative Controls for Positive Findings

Positive Controls for Negative Findings

Quantification of Positive Findings

Regional Distribution

Cellular Distribution

Subcellular Distribution

Distribution of Other Molecular Components Involved in 2-AG Signaling

Conclusions

References

Pharmacological Tools in Endocannabinoid Neurobiology

Cannabinoid Receptor Ligands

Natural Products and Non-Selective Ligands

Classical Cannabinoids

Non-Classical Cannabinoids

Aminoalkylindoles

Eicosanoids

CB1-Selective Ligands

Agonists

Antagonists and Inverse Agonists

Allosteric Modulators

CB2-Selective Ligands

Agonists

Antagonists

Ligands of Other ECB Receptors

Modulators of ECB Metabolism

ECB Catabolism

Inhibition of Anandamide Transport

FAAH Inhibitors

MGL Inhibitors

NAAA Inhibitors

ECB Synthesis

References

Genetic Models of the Endocannabinoid System

Introduction

Genetic Models

Available Tools

Null Mutant Mouse Lines

Conditional CB1 Receptor Mutants

Complications with Cre Recombinase-Expressing Lines

Methodological Considerations on Behavioural Experiments with Mutant Mice

Caveats in Genetics and Pharmacology

Perspectives

References

Endocannabinoid Signaling in Neural Plasticity

Introduction

Definitions, Scope, Limitations, and Caveats

ECBs: Basic Principles

ECBs Regulate Synaptic Plasticity

Short-Term Plasticity

Short-Term Target-Dependent Plasticity

Long-Term Plasticity

Striatum

Nucleus Accumbens (NAc)

Hippocampus

Cerebellum

Amygdala

Ventral Tegmental Area (VTA)

Cortex

Mechanisms of ECB-Dependent Long-Term Plasticity

Sufficiency of CB1R Activation for ECB-LTD(or -iLTD) Induction

Molecular Mechanisms of ECB-LTD (or iLTD) Maintenance

Spike-Timing Dependent Plasticity (STDP)

Interneurons Mobilize ECBs

Plasticity of the ECB System

Use-Dependence of CB1R Efficacy

Tonic CB1R Activation and ECB Regulation

Plasticity of ECB Mobilization

ECB Transport as a Synaptically Modifiable Process

The ECB System and Seizures

Interactions Between AEA and 2-AG

Conclusion

References

Lessons from Nonmammalian Species

Invertebrates

Insects

Ants

Aquatic Invertebrates and Annelids

Hydra (Hydra Vulgaris)

Planaria

Leech

Snail

Sea Urchin

Urochordates Including the Sea Squirt (Ciona intestinalis)

Nonmammalian Vertebrates

Fish

Amphibians

Birds

Lessons Learned

References

Physiology and Pathophysiology

Roles of the Endocannabinoid System in Learning and Memory

Introduction

Expression of Cannabinoid Receptors in the Brain: Focus on CB1

The ECS and Learning and Memory

Pharmacology of Exogenous Cannabinoid Agonists and Physiology of the ECS: Important Differences in Complex Functions

Involvement of the Endocannabinoid System in Learning and Memory

The ECS and Working Memory

The ECS and Long-Term Memories

The ECS and ``Declarative´´-Type Memories

The ECS and Recognition Memory

The ECS and Spatial Memory

The ECS and Procedural Memory

The ECS and Operant Conditioning

The ECS and Habits

The ECS and Procedural Strategies in a Spatial Task

The ECS and Emotional Memory

The ECS and Aversive Memory

The ECS and Fear Memory

Acquisition of Fear Memories

Consolidation, Re-consolidation and Extinction of Fear Memories

Intracellular Cascades

A Possible Mechanism for ECS-Dependent Extinction of Fear Memories in the Amygdala

General Conclusions

References

Endocannabinoids and the Non-Homeostatic Control of Appetite

Obesity and the Problem of Homeostasis

Eating for Survival

Gluttony and Externality

Endocannabinoids in Food Craving, Anticipation and Palatability

THC Hyperphagia

Orexigenic Actions of the Endocannabinoids

Behavioural Characterization of Cannabinoid Hyperphagia: The Reward Hypothesis

Endocannabinoids and ``Wanting´´: Primary Motivational Actions

Endocannabinoids and ``Liking´´: Secondary Motivational Actions

Endocannabinoid-Opioid Interactions in Eating Motivation

Endocannabinoids and Interactions with Other Orexigens

Conclusion

References

Cannabinoid/Endocannabinoid Signaling Impact on Early Pregnancy Events

Introduction

Endocannabinoid Systems

AEA Synthesis and Degradation

2AG Synthesis and Degradation

Cannabinoid Receptors

Peri-implantation Events

Preimplantation Embryo Development

Oviductal-Uterine Embryo Transport

Implantation

Conclusion

References

Targeting the Cannabinoid System to Produce Analgesia

Introduction

The Endogenous Cannabinoid System

Endocannabinoids

Endocannabinoid Synthesis

Endocannabinoid Metabolism

Endocannabinoids and Pain Processing

CB Receptor-Mediated Analgesia

Attenuation of Endocannabinoid Catabolism Produces Analgesia

Arthritis - A Therapeutic Target for Cannabinoids?

References

Integration of Endocannabinoid Signaling into the Neural Network Regulating Stress-Induced Activation of the Hypothal

Stress and the Hypothalamic-Pituitary-Adrenal Axis

The Endocannabinoid System

Endocannabinoid-Mediated Regulation of the HPA Axis

Endocannabinoid Signaling within the HPA Axis

Endocannabinoid Signaling Inhibits HPA Axis Activity

At What Sites of Action Does Endocannabinoid Signaling Modulate HPA Axis Activity?

Acute Stress-Induced Modulation of Endocannabinoid Signaling: Contributions to Glucocorticoid Negative Feedback

Chronic Stress-Induced Regulation of Endocannabinoid Signaling: A Driving Force for Stress Habituation

Conclusion

References

Pathology

Drug Addiction

Introduction

Drug Addiction

Endocannabinoid System in Brain Reward Circuitry

Release of Endocannabinoids by Abused Drugs

Endocannabinoids in Drug-Seeking and Relapse

Cannabinoids

Self-Administration of Cannabinoids

Drug Self-Administration Paradigm

Fixed-Ratio Schedule

Second-Order Schedule and Drug Seeking

Conditioned Place Preference and Aversion with Cannabinoids

THC and Synthetic Cannabinoids

AEA

Discriminative-Stimulus Effects of Cannabinoids

Tolerance, Physical Dependence and Behavioral Sensitization

Tolerance

Physical Dependence

Behavioral Sensitization

Opioids

Alcohol

Nicotine

Psychostimulants

Cocaine and Methylphenidate

Cocaine

Methylphenidate

Amphetamine, Methamphetamine and 3,4-Methylendioxymethamphetamine (MDMA)

Endocannabinoid System and Treatment of Drug Addiction

References

Role of Endocannabinoid Signaling in Anxiety and Depression

Human Studies Suggesting a Role for Endocannabinoid Signaling in Anxiety

Animal Studies Indicating a Role for ECS in Anxiety

Effects of CB1 Receptor Blockade and Genetic Deletion on Unconditioned Anxiety Behaviors

Effects of Pharmacological and Genetic Augmentation of ECS on Unconditioned Anxiety Behaviors

Effects of CB1 Receptor Deletion and Pharmacological Blockade on Conditioned Anxiety Behaviors

Effects of ECS Augmentation on Conditioned Anxiety Behaviors

Neural Mechanisms Underlying Endocannabinoid Modulation of Anxiety

Human Studies Suggesting a Role for ECS in Depression

Cannabis Use and Depression

Depression and the ECS

Animal Studies Suggesting a Role for ECS in Depression

Evidence That Alteration of CB1 Receptor Signaling Results in Anti-Depressant-Like Effects

Evidence That Environmental Contexts That Produce Depression-Like Symptoms Alter ECS

Evidence That Anti-Depressant Therapies Alter ECS

Neural Mechanisms Underlying Endocannabinoid Modulation of Depression

Clinical Implications for Endocannabinoid-Based Therapeutics for Anxiety and Depressive Disorders

References

Feeding Disorders and Obesity

Introduction

Historical Background

Modes of Action by which Endocannabinoids Promote Energy Storage

Endocannabinoids Promote Energy Storage in the Brain

Endocannabinoids Promote Energy Storage at a Peripheral Level

Adipose Tissue

Liver

Skeletal Muscle

Endocrine Pancreas

Obesity as a Disease Model of Endocannabinoid Overactivation

Endocannabinoids and Central Eating Disorders

How CB1 Receptor Antagonism May Act Against Obesity and Metabolic Complications

Pharmacological Implications in Humans

Rimonabant

Taranabant

Conclusions

References

Schizophrenia

Introduction

Neurobiology of the Endocannabinoid System in Schizophrenia

Animal Studies

Human Post-Mortem Studies

Clinical Studies

Cannabis Administration

Conclusions and Model

References

Tourette´s Syndrome

Tourette´s Syndrome

The Clinical Picture of Tourette´s Syndrome

The Aetiology of Tourette´s Syndrome

Treatment of Tourette´s Syndrome

Future Perspectives in the Treatment of Tourette´s Syndrome

Treatment of Tourette´s Syndrome with Cannabinoids

Anecdotal Reports

Uncontrolled Single Case Studies

Controlled Single-Dose Trial

Six-Week Randomized Trial

Adverse Effects

Central Cannabinoid Receptor (CNR1) Gene in Tourette´s Syndrome

In Vivo Imaging of Central Cannabinoid CB1 Receptors in TS Using [123I]AM281 and SPECT

Possible Explanations for Beneficial Effects of Cannabinoids in TS

Conclusions and Perspective

References

Index