title: Lack of hippocampal CB1 receptor desensitization by Δ(9)-tetrahydrocannabinol in aged mice and by low doses of JZL 184.
abstract: Activation of cannabinoid CB1 receptors may offer new therapeutic strategies, but the efficiency of CB1 receptor agonists may be impaired by tolerance development upon prolonged administration. We compared the influence of repeated administration of Δ(9)-tetrahydrocannabinol (THC) 10 mg/kg on the motility and on basal and CB1 receptor-stimulated (35)S-GTPγS binding of adolescent and aged mice. Moreover, we determined the influence of JZL 184 (which inhibits the 2-arachidonoylglycerol, 2-AG, degrading enzyme monoacylglycerol lipase, MAGL) on (35)S-GTPγS binding and 2-AG levels of young adult mice. Mouse motility was tested in the open field. (35)S-GTPγS binding was studied in hippocampal membranes. THC and CP 55,940 were used as cannabinoid agonists in the behavioural and biochemical studies, respectively. 2-AG levels were quantified by liquid chromatography-multiple reaction monitoring. The THC (10 mg/kg)-induced hypomotility was stronger in untreated than in THC-pretreated adolescent mice but similar in both treatment groups of aged mice. Basal and stimulated (35)S-GTPγS binding was decreased in membranes from THC-pretreated adolescent but not affected in membranes from aged mice. Treatment of young adult mice with JZL 184 (4, 10 and 40 mg/kg) for 14 days did not affect basal binding. Stimulated binding tended to be decreased by 25 % only in mice treated with JZL 184 (40 mg/kg). Hippocampal 2-AG level was increased by JZL 184 at 40 and 10 but not affected at 4 mg/kg. In conclusion, CB1 receptor tolerance does not occur in aged mice pretreated with THC and in young adult mice treated with a low dose of the MAGL inhibitor JZL 184.
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Feliszek
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128, Mainz, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Bindila
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128, Mainz, Germany.
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.affiliation: Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
authors.forename: Andras
authors.initials: A
authors.lastname: Bilkei-Gorzo
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany. e.schlicker@uni-bonn.de.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schlicker
mesh_terms: D000367:Age Factors; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D052117:Benzodioxoles / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D004361:Drug Tolerance; D063388:Endocannabinoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005838:Genotype; D005989:Glycerides / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D010641:Phenotype; D010880:Piperidines / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; C578453:CNR1 protein, mouse; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; C534333:JZL 184; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013759:Dronabinol; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases
keywords: 2-Arachidonoylglycerol (2-AG); 35S-GTPγS binding; Hippocampus; JZL 184; Open-field activity; Δ9-Tetrahydrocannabinol (THC)