1;Behavioral Neurobiology of the Endocannabinoid System;3 1.1;Preface;5 1.2;Contents;6 1.3;Biochemistry, Pharmacology, Genetics & Chemistry;12 1.3.1;The Life Cycle of the Endocannabinoids: Formation and Inactivation;13 1.3.1.1;Cannabinoid Signalling in the CNS;15 1.3.1.2;What Are Endocannabinoids?;15 1.3.1.3;Ester Endocannabinoids;16 1.3.1.3.1;Synthesis of Ester Endocannabinoids;16 1.3.1.3.1.1;Regulation of Phospholipase C Activity;19 1.3.1.3.1.2;Regulation of DGL Activity;19 1.3.1.3.1.3;Alternative Pathways of DAG and 2AG Synthesis;20 1.3.1.3.2;Hydrolysis of Ester Endocannabinoids;22 1.3.1.4;Amide Endocannabinoids;24 1.3.1.4.1;Synthesis of NAPEs;24 1.3.1.4.2;Synthesis of Amide Endocannabinoids;25 1.3.1.4.2.1;Pharmacological and Biochemical Manipulation of NAPE-PLD Activity;26 1.3.1.4.2.2;Alternative Pathways of Amide ECB Generation;28 1.3.1.4.3;Hydrolysis of Amide Endocannabinoids;30 1.3.1.4.3.1;FAAH1 Activity;30 1.3.1.4.3.2;FAAH2 Activity;31 1.3.1.4.3.3;NAAA Activity;32 1.3.1.5;Other Routes of ECB Transformation;32 1.3.1.5.1;Oxidative Metabolism of ECBs;33 1.3.1.5.1.1;Cyclooxygenase Activity;33 1.3.1.5.1.2;Lipoxygenase Activity;34 1.3.1.5.1.3;Cytochrome P450s and Epoxygenase Activity;34 1.3.1.6;Stimulation of ECB Synthesis and Release;35 1.3.1.7;Conclusion;37 1.3.1.8;References;37 1.3.2;Endocannabinoid Receptor Pharmacology;46 1.3.2.1;GPCR Overview;47 1.3.2.2;Receptor Pharmacology;48 1.3.2.2.1;GPCR Signaling;48 1.3.2.2.2;Radioligand Binding;49 1.3.2.2.3;GTPgammaS Binding as a Measure of GPCR Function;50 1.3.2.3;CB1 Receptor Gene Structure;53 1.3.2.3.1;Chromosomal Structure, Potential Alternative Splicing;53 1.3.2.3.2;CNR1 Polymorphisms;53 1.3.2.4;CB2 Receptor Gene Structure;54 1.3.2.4.1;CB2 Receptor Chromosomal Localization and Potential Alternative Splicing;54 1.3.2.4.2;CNR2 Polymorphisms;55 1.3.2.5;Structural Characteristics of the CB1 Receptor;55 1.3.2.6;Structural Characteristics of the CB2 Receptor;57 1.3.2.7;CB1 and CB2 Receptor Localization;58 1.3.2.8;Cellular Signaling of CB1 and CB2 Receptors;58 1.3.2.8.1;Inhibition of Adenylyl Cyclase - Gi/o Coupling of CB1 and CB2 Receptors;58 1.3.2.8.2;Cannabinoid Receptor Activation of MAP Kinases;59 1.3.2.8.3;Crosstalk Between Cannabinoid and Other Receptors;59 1.3.2.8.4;Transactivation Between Cannabinoid Receptors and Tyrosine Kinase Receptors;59 1.3.2.8.5;Cannabinoid Receptor-Mediated Modulation of Ion Channels;60 1.3.2.9;Implications of Constitutive Receptor Activity, Protean Agonism, and Inverse Agonism;60 1.3.2.10;Cannabinoid Receptor Ligands;62 1.3.2.10.1;Non-Selective CB1/CB2 Receptor Agonists;62 1.3.2.10.2;CB1 Receptor Antagonists;64 1.3.2.10.3;CB2 Receptor Agonists;64 1.3.2.10.4;CB2 Receptor Antagonists;65 1.3.2.10.5;Allosteric Modulators of Cannabinoid Receptors;65 1.3.2.11;Non-CB1/Non-CB2 Receptors;66 1.3.2.11.1;GPR55;66 1.3.2.11.2;Interactions of Cannabinoids with Ion Channels;66 1.3.2.12;Conclusions;67 1.3.2.13;References;67 1.3.3;Endocannabinoid Receptors: CNS Localization of the CB1 Cannabinoid Receptor;73 1.3.3.1;Introduction;74 1.3.3.2;Methodological Considerations for Localization Studies on the Endocannabinoid System;76 1.3.3.2.1;Negative Controls for Positive Findings;76 1.3.3.2.2;Positive Controls for Negative Findings;77 1.3.3.2.3;Quantification of Positive Findings;78 1.3.3.3;Regional Distribution;78 1.3.3.4;Cellular Distribution;82 1.3.3.5;Subcellular Distribution;84 1.3.3.6;Distribution of Other Molecular Components Involved in 2-AG Signaling;87 1.3.3.7;Conclusions;88 1.3.3.8;References;90 1.3.4;Pharmacological Tools in Endocannabinoid Neurobiology;95 1.3.4.1;Cannabinoid Receptor Ligands;96 1.3.4.2;Natural Products and Non-Selective Ligands;97 1.3.4.2.1;Classical Cannabinoids;98 1.3.4.2.2;Non-Classical Cannabinoids;98 1.3.4.2.3;Aminoalkylindoles;99 1.3.4.2.4;Eicosanoids;99 1.3.4.3;CB1-Selective Ligands;100 1.3.4.3.1;Agonists;100 1.3.4.3.2;Antagonists and Inverse Agonists;100 1.3.4.3.3;Allosteric Modulators;102 1.3.4.4;CB2-Selective Ligands;103 1.3.4.4.