title: Chronic and acute adenosine A2Areceptor blockade prevents long-term episodic memory disruption caused by acute cannabinoid CB1receptor activation.
abstract: Cannabinoid-mediated memory impairment is a concern in cannabinoid-based therapies. Caffeine exacerbates cannabinoid CB1receptor (CB1R)-induced memory deficits through an adenosine A1receptor-mediated mechanism. We now evaluated how chronic or acute blockade of adenosine A2Areceptors (A2ARs) affects long-term episodic memory deficits induced by a single injection of a selective CB1R agonist. Long-term episodic memory was assessed by the novel object recognition (NOR) test. Mice received an intraperitoneal (i.p.) injection of the CB1/CB2receptor agonist WIN 55,212-2 (1 mg/kg) immediately after the NOR training, being tested for novelty recognition 24 h later. Anxiety levels were assessed by the Elevated Plus Maze test, immediately after the NOR. Mice were also tested for exploratory behaviour at the Open Field. For chronic A2AR blockade, KW-6002 (istradefylline) (3 mg/kg/day) was administered orally for 30 days; acute blockade of A2ARs was assessed by i.p. injection of SCH 58261 (1 mg/kg) administered either together with WIN 55,212-2 or only 30 min before the NOR test phase. The involvement of CB1Rs was assessed by using the CB1R antagonist, AM251 (3 mg/kg, i.p.). WIN 55,212-2 caused a disruption in NOR, an action absent in mice also receiving AM251, KW-6002 or SCH 58261 during the encoding/consolidation phase; SCH 58251 was ineffective if present during retrieval only. No effects were detected in the Elevated Plus maze or Open Field Test. The finding that CB1R-mediated memory disruption is prevented by antagonism of adenosine A2ARs, highlights a possibility to prevent cognitive side effects when therapeutic application of CB1R drugs is desired.
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal.
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Mouro
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal.
authors.forename: Vânia L
authors.initials: VL
authors.lastname: Batalha
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Ferreira
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal.
authors.forename: Joana E
authors.initials: JE
authors.lastname: Coelho
authors.affiliation: Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie I, University of Bonn, Germany; Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman.
authors.forename: Younis
authors.initials: Y
authors.lastname: Baqi
authors.affiliation: Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie I, University of Bonn, Germany.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal.
authors.forename: Luísa V
authors.initials: LV
authors.lastname: Lopes
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal.
authors.forename: Joaquim A
authors.initials: JA
authors.lastname: Ribeiro
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal. Electronic address: anaseb@medicina.ulisboa.pt.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sebastião
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage*; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000633:toxicity*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D061212:Memory, Episodic; D057567:Memory, Long-Term / Q000187:drug effects* / Q000502:physiology; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011687:Purines / Q000008:administration & dosage; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D014230:Triazoles / Q000008:administration & dosage
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D048588:Benzoxazines; C578453:CNR1 protein, mouse; D002121:Calcium Channel Blockers; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D043884:Receptor, Cannabinoid, CB1; D014230:Triazoles; C111599:istradefylline; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
keywords: Adenosine A(2A) receptor; Caffeine; Cannabinoid receptor 1; Istradefylline; Memory; Novel object recognition