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

Neuropharmacology. 2017 May 1:117:316-327. doi: 10.1016/j.neuropharm.2017.02.021. Epub 2017 Feb 21.


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.

Keywords: Adenosine A(2A) receptor; Caffeine; Cannabinoid receptor 1; Istradefylline; Memory; Novel object recognition.

MeSH terms

  • Adenosine A2 Receptor Antagonists / administration & dosage*
  • Animals
  • Benzoxazines / pharmacology
  • Calcium Channel Blockers / pharmacology
  • Cannabinoid Receptor Agonists / toxicity*
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory Disorders / chemically induced
  • Memory Disorders / metabolism
  • Memory Disorders / prevention & control*
  • Memory, Episodic*
  • Memory, Long-Term / drug effects*
  • Memory, Long-Term / physiology
  • Mice, Inbred C57BL
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Piperidines / pharmacology
  • Purines / administration & dosage
  • Pyrazoles / pharmacology
  • Pyrimidines / administration & dosage
  • Receptor, Adenosine A2A / metabolism
  • Receptor, Cannabinoid, CB1 / agonists*
  • Receptor, Cannabinoid, CB1 / metabolism
  • Recognition, Psychology / drug effects
  • Recognition, Psychology / physiology
  • Triazoles / administration & dosage


  • 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine
  • Adenosine A2 Receptor Antagonists
  • Benzoxazines
  • CNR1 protein, mouse
  • Calcium Channel Blockers
  • Cannabinoid Receptor Agonists
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Purines
  • Pyrazoles
  • Pyrimidines
  • Receptor, Adenosine A2A
  • Receptor, Cannabinoid, CB1
  • Triazoles
  • istradefylline
  • AM 251
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone