From the department of experimental medicine and public health, University of Camerino, Italy




НазваниеFrom the department of experimental medicine and public health, University of Camerino, Italy
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From the DEPARTMENT OF EXPERIMENTAL MEDICINE AND PUBLIC HEALTH, University of Camerino, Italy


Role of the endocannabinoid system in the control of alcohol abuse mechanisms


Andrea Cippitelli





Supervisors:


  • Prof. Roberto Ciccocioppo

  • Prof. Fernando Rodriguez de Fonseca



Camerino 2006


List of Papers


This thesis is based on the papers listed below:



  1. Rodriguez de fonseca F., Del Arco I., Bermudez-Silva FJ., Bilbao A., Cippitelli A., Navarro M. The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol. Jan-Feb; 40 (1): 2-14, 2005. Review.




  1. Cippitelli A., Bilbao A., Hansson A.C., Del Arco I., Sommer W., Heilig M., Massi M., Bermudez-Silva F.J., Navarro M., Ciccocioppo R., de Fonseca F.R.; The European TARGALC Consortium. Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats. Eur J Neurosci. Apr; 21(8): 2243-51, 2005.




  1. Pavon F.J., Bilbao A., Hernández-Folgado L., Cippitelli A., Jagerovic N., Abellán G., Rodríguez-Franco M.I., Serrano A., Macias M., Gómez R., Navarro M., Goya, P. and Rodríguez de Fonseca F. Pharmacological evaluation of the novel in vivo cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole – LH 21 –on food intake: evidence for a peripheral site of action. Manuscript submitted to second revision at Neuropharmacology.




  1. Cippitelli A., Bilbao A., Navarro M.,Gorriti M.A., Massi M., Pomelli D., Ciccocioppo R. and Rodríguez de Fonseca F.. Selective reduction of ethanol self-administration by the Anandamide trasport inhibitor AM 404. Manuscript submitted to second revision at Eur J Neurosci.



Table of contents


I. INTRODUCTION 6

Cannabis history and use 6

Endocannabinoid system 7

Cannabinoids and alcohol links 8

Animal and experimental models 10

Aim and contents 11

References 13


II. THE ENDOCANNABINOID SYSTEM: PHYSIOLOGY AND PHARMACOLOGY 18

Abstract 18

Introduction 18

Biochemistry of the endogenous cannabinoid system 19

Functional neuroanatomy of the endogenous cannabinoid system 23

Pharmacology of the endogenous cannabinoid system 25

Physiology of the endogenous cannabinoid system 28

A practical approach: role for the endocannabinoid system in alcoholism 31

Conclusion 31

References 32


III. CANNABINOID CB1 RECEPTOR ANTAGONISM REDUCES CONDITIONED REINSTATEMENT OF ETHANOL-SEEKING BEHAVIOUR IN RATS 41

Abstract 41

Introduction 41

Materials and Methods 42

Results 45

Discussion 51

References 54


IV. PHARMACOLOGICAL EVALUATION OF THE NOVEL IN VIVO CANNABINOID RECEPTOR ANTAGONIST 5-(4-CHLOROPHENYL)-1-(2,4-DICHLOROPHENYL)-3-HEXYL-1H-1,2,4-TRIAZOLE – LH 21 – ON FOOD INTAKE: EVIDENCE FOR A PERIPHERAL SITE OF ACTION 58

Abstract 58

Introduction 58

Materials and Methods 60

Results 63

Discussion 70

References 72


V. SELECTIVE REDUCTION OF ETHANOL SELF-ADMINISTRATION BY THE ANANDAMIDE TRANSPORT INHIBITOR AM 404 76

Abstract 76

Introduction 76

Materials and Methods 78

Results 81

Discussion 88

References 90


VI. PPAR-α AGONISTS MODULATE ALCOHOL CRAVING AND RELAPSE THROUGH A PERIPHERAL MECHANISM 94

Introduction 94

Materials and Methods 95

Results 98

Discussion 102

References 104


VII. GENERAL DISCUSSION 107

References 109


ACKNOWLEDGEMENTS 110


I

I.INTRODUCTION


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