Itisabundantlyclearthattheendocannabinoidsignallingsystemisubiquitously expressedthroughouttheanimalkingdomfromsimpleinvertebratestoman,and thatitisrepresentedinalmosteverycelltype. Thecomponentsofthesysteminrelationtothesynthesisandmetabolismofthe endocannabinoidsandtheirbiologicaltargetsarebeginningtobeunravelled,but the degree of complexity involved is enormous. This is particularly true for endocannabinoidsignallinginthecentralnervoussystem,whichisthesubjectof thisvolume. Inthebook,avarietyofauthors,whoareallveryactiveresearchersinthe?eld, providecurrentaccountsoftherolesoftheendocannabinoidsysteminnormalbrain physiologyinrelationtotheneurobiologyofessentialbehaviorsandinanumberof centraldiseasestates. The?rstpartprovidesabackgroundand"toolbox",detailingwhatisknown abouttheendocannabinoidsthemselvesandtheirtargetreceptorsandhowthey in?uencesynapticactivity. Itgoesontodescribethegeneticandpharmacological methodsavailableforinvestigatingthesystem. The second part describes endocannabinoid roles in key systems controlling appetite,pain,memoryandlearning,stressresponsesandreproduction. The?nalgroupofchaptersreviewsthecurrentstateofknowledgesurrounding thefunctionoftheendocannabinoidsystemindepression,drugaddiction,schi- phrenia,feedingdisordersandTourette'ssyndrome.Giventheenormousamountofinformationavailableandtherateofprogressin research,itisimpossibleforthevolumetobetotallycomprehensive,butwetrust thatitwillprovideanexcellentbackgroundtoresearcherswantingtoexpandtheir areaofinterestandtonewcomerstothe?eld. Nottingham,UnitedKingdom DavidKendall StephenAlexander v Contents PartI Biochemistry,Pharmacology,GeneticsandChemistry 1 TheLifeCycleoftheEndocannabinoids:Formation andInactivation...3 StephenP. H. AlexanderandDavidA. Kendall 2 EndocannabinoidReceptorPharmacology ...37 KenMackieandBettyYao 3 EndocannabinoidReceptors:CNSLocalizationoftheCB 1 CannabinoidReceptor...65 Istva'nKatona 4 PharmacologicalToolsinEndocannabinoidNeurobiology...87 MarcoMorandAlessioLodola 5 GeneticModelsoftheEndocannabinoidSystem ...111 KrisztinaMonoryandBeatLutz 6 EndocannabinoidSignalinginNeuralPlasticity ...141 BradleyE. Alger 7 LessonsfromNonmammalianSpecies ...173 KenSoderstrom PartII PhysiologyandPathophysiology 8 RolesoftheEndocannabinoidSysteminLearning andMemory ...201 GiovanniMarsicanoandPaulineLafenetre vii viii Contents 9 EndocannabinoidsandtheNon-HomeostaticControl ofAppetite ...231 TimC.Kirkham 10 Cannabinoid/EndocannabinoidSignalingImpactonEarly PregnancyEvents...255 XiaofeiSunandSudhansuK. Dey 11 TargetingtheCannabinoidSystemtoProduceAnalgesia ...275 DeviRaniSagar,MaulikJhaveri,andVictoriaChapman 12 IntegrationofEndocannabinoidSignalingintotheNeural NetworkRegulatingStress-InducedActivationofthe Hypothalamic-Pituitary-AdrenalAxis ...289 BorisB. GorzalkaandMatthewN. Hill PartIII Pathology 13 DrugAddiction ...309 ZuzanaJustinova,LeighV. Panlilio,andStevenR. Goldberg 14 RoleofEndocannabinoidSignalinginAnxietyandDepression...347 SachinPatelandCeciliaJ. Hillard 15 FeedingDisordersandObesity...373 CristinaCervino,ValentinaVicennati,RenatoPasquali, andUbertoPagotto 16 Schizophrenia...387 F. Markus 17 Tourette'sSyndrome...397 KirstenR. Mu..ller-Vahl Index ...411 Contributors StephenP. H. Alexander SchoolofBiomedicalSciencesandInstituteofNeuroscience,UniversityofN- tingham Medical School, Queens Medical Centre, Nottingham NG7 2UH, UK; steve. alexander@nottingham. ac. uk BradleyE. Alger Departments of Physiology and Psychiatry, University of Maryland School of Medicine, 655 W. Baltimore St. /BRB 5-025, Baltimore, MD 21201, USA; balger@umaryland. edu CristinaCervino Endocrinology Unit and Center of Applied Biomedical Research (C.R. B. A. ), DepartmentofInternalMedicineandGastroenterology,S. Orsola-MalpighiHos- tal,AlmaMaterStudiorumUniversityofBologna,40138Bologna,Italy VictoriaChapman SchoolofBiomedicalSciences,UniversityofNottingham,NottinghamNG72UH, UK;victoria. chapman@nottingham. ac. uk SudhansuK. Dey Departments of Pharmacology, Pediatrics and Cell & Developmental Biology, Division of Reproductive and Developmental Biology, Vanderbilt University MedicalCenter,Nashville,TN37232,USA;sk. dey@vanderbilt. edu StevenR.

Itisabundantlyclearthattheendocannabinoidsignallingsystemisubiquitously expressedthroughouttheanimalkingdomfromsimpleinvertebratestoman,and thatitisrepresentedinalmosteverycelltype. Thecomponentsofthesysteminrelationtothesynthesisandmetabolismofthe endocannabinoidsandtheirbiologicaltargetsarebeginningtobeunravelled,but the degree of complexity involved is enormous. This is particularly true for endocannabinoidsignallinginthecentralnervoussystem,whichisthesubjectof thisvolume. Inthebook,avarietyofauthors,whoareallveryactiveresearchersinthe?eld, providecurrentaccountsoftherolesoftheendocannabinoidsysteminnormalbrain physiologyinrelationtotheneurobiologyofessentialbehaviorsandinanumberof centraldiseasestates. The?rstpartprovidesabackgroundand"toolbox",detailingwhatisknown abouttheendocannabinoidsthemselvesandtheirtargetreceptorsandhowthey in?uencesynapticactivity. Itgoesontodescribethegeneticandpharmacological methodsavailableforinvestigatingthesystem. The second part describes endocannabinoid roles in key systems controlling appetite,pain,memoryandlearning,stressresponsesandreproduction. The?nalgroupofchaptersreviewsthecurrentstateofknowledgesurrounding thefunctionoftheendocannabinoidsystemindepression,drugaddiction,schi- phrenia,feedingdisordersandTourette'ssyndrome.Giventheenormousamountofinformationavailableandtherateofprogressin research,itisimpossibleforthevolumetobetotallycomprehensive,butwetrust thatitwillprovideanexcellentbackgroundtoresearcherswantingtoexpandtheir areaofinterestandtonewcomerstothe?eld. Nottingham,UnitedKingdom DavidKendall StephenAlexander v Contents PartI Biochemistry,Pharmacology,GeneticsandChemistry 1 TheLifeCycleoftheEndocannabinoids:Formation andInactivation...3 StephenP. H. AlexanderandDavidA. Kendall 2 EndocannabinoidReceptorPharmacology ...37 KenMackieandBettyYao 3 EndocannabinoidReceptors:CNSLocalizationoftheCB 1 CannabinoidReceptor...65 Istva'nKatona 4 PharmacologicalToolsinEndocannabinoidNeurobiology...87 MarcoMorandAlessioLodola 5 GeneticModelsoftheEndocannabinoidSystem ...111 KrisztinaMonoryandBeatLutz 6 EndocannabinoidSignalinginNeuralPlasticity ...141 BradleyE. Alger 7 LessonsfromNonmammalianSpecies ...173 KenSoderstrom PartII PhysiologyandPathophysiology 8 RolesoftheEndocannabinoidSysteminLearning andMemory ...201 GiovanniMarsicanoandPaulineLafenetre vii viii Contents 9 EndocannabinoidsandtheNon-HomeostaticControl ofAppetite ...231 TimC.Kirkham 10 Cannabinoid/EndocannabinoidSignalingImpactonEarly PregnancyEvents...255 XiaofeiSunandSudhansuK. Dey 11 TargetingtheCannabinoidSystemtoProduceAnalgesia ...275 DeviRaniSagar,MaulikJhaveri,andVictoriaChapman 12 IntegrationofEndocannabinoidSignalingintotheNeural NetworkRegulatingStress-InducedActivationofthe Hypothalamic-Pituitary-AdrenalAxis ...289 BorisB. GorzalkaandMatthewN. Hill PartIII Pathology 13 DrugAddiction ...309 ZuzanaJustinova,LeighV. Panlilio,andStevenR. Goldberg 14 RoleofEndocannabinoidSignalinginAnxietyandDepression...347 SachinPatelandCeciliaJ. Hillard 15 FeedingDisordersandObesity...373 CristinaCervino,ValentinaVicennati,RenatoPasquali, andUbertoPagotto 16 Schizophrenia...387 F. Markus 17 Tourette'sSyndrome...397 KirstenR. Mu..ller-Vahl Index ...411 Contributors StephenP. H. Alexander SchoolofBiomedicalSciencesandInstituteofNeuroscience,UniversityofN- tingham Medical School, Queens Medical Centre, Nottingham NG7 2UH, UK; steve. alexander@nottingham. ac. uk BradleyE. Alger Departments of Physiology and Psychiatry, University of Maryland School of Medicine, 655 W. Baltimore St. /BRB 5-025, Baltimore, MD 21201, USA; balger@umaryland. edu CristinaCervino Endocrinology Unit and Center of Applied Biomedical Research (C.R. B. A. ), DepartmentofInternalMedicineandGastroenterology,S. Orsola-MalpighiHos- tal,AlmaMaterStudiorumUniversityofBologna,40138Bologna,Italy VictoriaChapman SchoolofBiomedicalSciences,UniversityofNottingham,NottinghamNG72UH, UK;victoria. chapman@nottingham. ac. uk SudhansuK. Dey Departments of Pharmacology, Pediatrics and Cell & Developmental Biology, Division of Reproductive and Developmental Biology, Vanderbilt University MedicalCenter,Nashville,TN37232,USA;sk. dey@vanderbilt. edu StevenR.

Itisabundantlyclearthattheendocannabinoidsignallingsystemisubiquitously expressedthroughouttheanimalkingdomfromsimpleinvertebratestoman,and thatitisrepresentedinalmosteverycelltype. Thecomponentsofthesysteminrelationtothesynthesisandmetabolismofthe endocannabinoidsandtheirbiologicaltargetsarebeginningtobeunravelled,but the degree of complexity involved is enormous. This is particularly true for endocannabinoidsignallinginthecentralnervoussystem,whichisthesubjectof thisvolume. Inthebook,avarietyofauthors,whoareallveryactiveresearchersinthe?eld, providecurrentaccountsoftherolesoftheendocannabinoidsysteminnormalbrain physiologyinrelationtotheneurobiologyofessentialbehaviorsandinanumberof centraldiseasestates. The?rstpartprovidesabackgroundand"toolbox",detailingwhatisknown abouttheendocannabinoidsthemselvesandtheirtargetreceptorsandhowthey in?uencesynapticactivity. Itgoesontodescribethegeneticandpharmacological methodsavailableforinvestigatingthesystem. The second part describes endocannabinoid roles in key systems controlling appetite,pain,memoryandlearning,stressresponsesandreproduction. The?nalgroupofchaptersreviewsthecurrentstateofknowledgesurrounding thefunctionoftheendocannabinoidsystemindepression,drugaddiction,schi- phrenia,feedingdisordersandTourette'ssyndrome.Giventheenormousamountofinformationavailableandtherateofprogressin research,itisimpossibleforthevolumetobetotallycomprehensive,butwetrust thatitwillprovideanexcellentbackgroundtoresearcherswantingtoexpandtheir areaofinterestandtonewcomerstothe?eld. Nottingham,UnitedKingdom DavidKendall StephenAlexander v Contents PartI Biochemistry,Pharmacology,GeneticsandChemistry 1 TheLifeCycleoftheEndocannabinoids:Formation andInactivation...3 StephenP. H. AlexanderandDavidA. Kendall 2 EndocannabinoidReceptorPharmacology ...37 KenMackieandBettyYao 3 EndocannabinoidReceptors:CNSLocalizationoftheCB 1 CannabinoidReceptor...65 Istva'nKatona 4 PharmacologicalToolsinEndocannabinoidNeurobiology...87 MarcoMorandAlessioLodola 5 GeneticModelsoftheEndocannabinoidSystem ...111 KrisztinaMonoryandBeatLutz 6 EndocannabinoidSignalinginNeuralPlasticity ...141 BradleyE. Alger 7 LessonsfromNonmammalianSpecies ...173 KenSoderstrom PartII PhysiologyandPathophysiology 8 RolesoftheEndocannabinoidSysteminLearning andMemory ...201 GiovanniMarsicanoandPaulineLafenetre vii viii Contents 9 EndocannabinoidsandtheNon-HomeostaticControl ofAppetite ...231 TimC.Kirkham 10 Cannabinoid/EndocannabinoidSignalingImpactonEarly PregnancyEvents...255 XiaofeiSunandSudhansuK. Dey 11 TargetingtheCannabinoidSystemtoProduceAnalgesia ...275 DeviRaniSagar,MaulikJhaveri,andVictoriaChapman 12 IntegrationofEndocannabinoidSignalingintotheNeural NetworkRegulatingStress-InducedActivationofthe Hypothalamic-Pituitary-AdrenalAxis ...289 BorisB. GorzalkaandMatthewN. Hill PartIII Pathology 13 DrugAddiction ...309 ZuzanaJustinova,LeighV. Panlilio,andStevenR. Goldberg 14 RoleofEndocannabinoidSignalinginAnxietyandDepression...347 SachinPatelandCeciliaJ. Hillard 15 FeedingDisordersandObesity...373 CristinaCervino,ValentinaVicennati,RenatoPasquali, andUbertoPagotto 16 Schizophrenia...387 F. Markus 17 Tourette'sSyndrome...397 KirstenR. Mu..ller-Vahl Index ...411 Contributors StephenP. H. Alexander SchoolofBiomedicalSciencesandInstituteofNeuroscience,UniversityofN- tingham Medical School, Queens Medical Centre, Nottingham NG7 2UH, UK; steve. alexander@nottingham. ac. uk BradleyE. Alger Departments of Physiology and Psychiatry, University of Maryland School of Medicine, 655 W. Baltimore St. /BRB 5-025, Baltimore, MD 21201, USA; balger@umaryland. edu CristinaCervino Endocrinology Unit and Center of Applied Biomedical Research (C.R. B. A. ), DepartmentofInternalMedicineandGastroenterology,S. Orsola-MalpighiHos- tal,AlmaMaterStudiorumUniversityofBologna,40138Bologna,Italy VictoriaChapman SchoolofBiomedicalSciences,UniversityofNottingham,NottinghamNG72UH, UK;victoria. chapman@nottingham. ac. uk SudhansuK. Dey Departments of Pharmacology, Pediatrics and Cell & Developmental Biology, Division of Reproductive and Developmental Biology, Vanderbilt University MedicalCenter,Nashville,TN37232,USA;sk. dey@vanderbilt. edu StevenR.