title: Age-related changes of anandamide metabolism in CB1 cannabinoid receptor knockout mice: correlation with behaviour.
abstract: Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the most active endocannabinoids at brain (CB1) cannabinoid receptors. CD1 mice lacking the CB1 receptors ("knockout" [KO] mutants) were compared with wildtype (WT) littermates for their ability to degrade AEA through an AEA membrane transporter (AMT) and an AEA hydrolase (fatty acid amide hydrolase, FAAH). The age dependence of AMT and FAAH activity were investigated in 1- or 4-month-old WT and KO animals, and found to increase with age in KO, but not WT, mice and to be higher in the hippocampus than in the cortex of all animals. AEA and 2-AG were detected in nmol/mg protein (microm) concentrations in both regions, though the hippocampus showed approximately twice the amount found in the cortex. In the same regions, 2-AG failed to change across groups, while AEA was significantly decreased (approximately 30%) in hippocampus, but not in cortex, of old KO mice, when compared with young KO or age-matched WT animals. In the open-field test under bright light and in the lit-dark exploration model of anxiety, young KO mice, compared with old KO, exhibited a mild anxiety-related behaviour. In contrast, neither the increase in memory performance assessed by the object recognition test, nor the reduction of morphine withdrawal symptoms, showed age dependence in CB1 KO mice. These results suggest that invalidation of the CB1 receptor gene is associated with age-dependent adaptive changes of endocannabinoid metabolism which appear to correlate with the waning of the anxiety-like behaviour exhibited by young CB1 KO mice.
authors: Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Via Montpellier 1, I-00133 Rome, Italy. maccarone@med.uniroma2.it
authors: Mauro
authors: M
authors: Maccarrone
authors: Olga
authors: O
authors: Valverde
authors: Maria L
authors: ML
authors: Barbaccia
authors: Anna
authors: A
authors: Castañé
authors: Rafael
authors: R
authors: Maldonado
authors: Catherine
authors: C
authors: Ledent
authors: Marc
authors: M
authors: Parmentier
authors: Alessandro
authors: A
authors: Finazzi-Agrò
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D001923:Brain Chemistry / Q000235:genetics*; D063385:Cannabinoid Receptor Modulators; D002352:Carrier Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D063388:Endocannabinoids; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017288:Pain Threshold / Q000502:physiology; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000172:deficiency* / Q000235:genetics; D021641:Recognition, Psychology / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002352:Carrier Proteins; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide