title: CB1 cannabinoid receptors and on-demand defense against excitotoxicity.
abstract: Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant mice that lack expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory interneurons. In mutant mice,the excitotoxin kainic acid (KA) induced excessive seizures in vivo. The threshold to KA-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. KA administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wild-type principal hippocampal neurons. These protective mechanisms could not be triggered in mutant mice. The endogenous cannabinoid system thus provides on-demand protection against acute excitotoxicity in central nervous system neurons.
authors.affiliation: Molecular Genetics of Behaviour, Max-Planck-Institute of Psychiatry, Kraepelinstrabetae 2-10, 80804 Munich, Germany.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.forename: Sharon
authors.initials: S
authors.lastname: Goodenough
authors.forename: Krisztina
authors.initials: K
authors.lastname: Monory
authors.forename: Heike
authors.initials: H
authors.lastname: Hermann
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
authors.forename: Astrid
authors.initials: A
authors.lastname: Cannich
authors.forename: Shahnaz C
authors.initials: SC
authors.lastname: Azad
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cascio
authors.forename: Silvia Ortega
authors.initials: SO
authors.lastname: Gutiérrez
authors.forename: Mario
authors.initials: M
authors.lastname: van der Stelt
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: López-Rodriguez
authors.forename: Emilio
authors.initials: E
authors.lastname: Casanova
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Walter
authors.initials: W
authors.lastname: Zieglgänsberger
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Christian
authors.initials: C
authors.lastname: Behl
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism*; D063388:Endocannabinoids; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D005663:Furans / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D017781:Genes, Immediate-Early; D018698:Glutamic Acid / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D015398:Signal Transduction; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D019208:Brain-Derived Neurotrophic Factor; D002186:Cannabinoids; D063388:Endocannabinoids; D018690:Excitatory Amino Acid Agonists; D005663:Furans; D005989:Glycerides; C443680:N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide; D018696:Neuroprotective Agents; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C094503:glyceryl 2-arachidonate; D020928:Mitogen-Activated Protein Kinases; D000077285:Rimonabant; D007608:Kainic Acid; C078814:anandamide