Chronic and acute adenosine A_2A receptor blockade prevents long-term episodic memory disruption caused by acute cannabinoid CB₁ receptor activation

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 A_2A receptors (A_2ARs) 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 A_2AR blockade, KW-6002 (istradefylline) (3 mg/kg/day) was administered orally for 30 days; acute blockade of A_2ARs 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 A_2ARs, highlights a possibility to prevent cognitive side effects when therapeutic application of CB₁R drugs is desired.