Chronic and acute adenosine A2A receptor blockade prevents long-term episodic memory disruption caused by acute cannabinoid CB1 receptor activation

• Published in: Neuropharmacology 2017-05, Vol.117, p.316-327
• Main Authors: Mouro, Francisco M., Batalha, Vânia L., Ferreira, Diana G., Coelho, Joana E., Baqi, Younis, Müller, Christa E., Lopes, Luísa V., Ribeiro, Joaquim A., Sebastião, Ana M.
• Format: Article
• Language: English
• Subjects: Adenosine A2A receptor; Caffeine; Cannabinoid receptor 1; Istradefylline; Memory; Novel object recognition
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2017.02.021

Cannabinoid-mediated memory impairment is a concern in cannabinoid-based therapies. Caffeine exacerbates cannabinoid CB1 receptor (CB1R)-induced memory deficits through an adenosine A1 receptor-mediated mechanism. We now evaluated how chronic or acute blockade of adenosine A2A receptors (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/CB2 receptor 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. •Acute cannabinoid CB1 receptor activation disrupts long-term memory.•Adenosine A2A receptor blockade prevents CB1 receptor-mediated disruptive effects.•Both acute and chronic blockade of adenosine A2A receptors is effective.•A2A receptor blockade must occur during information coding/consolidation.•A2A receptor blockade only during retrieval is ineffective.