Adenosine A 2 A receptors are necessary and sufficient to trigger memory impairment in adult mice

Background and Purpose Caffeine (a non‐selective adenosine receptor antagonist) prevents memory deficits in aging and A lzheimer's disease, an effect mimicked by adenosine A 2 A receptor, but not A 1 receptor, antagonists. Hence, we investigated the effects of adenosine receptor agonists and antagonists on memory performance and scopolamine‐induced memory impairment in mice. Experimental Approach We determined whether A 2 A receptors are necessary for the emergence of memory impairments induced by scopolamine and whether A 2 A receptor activation triggers memory deficits in naïve mice, using three tests to assess short‐term memory, namely the object recognition task, inhibitory avoidance and modified Y ‐maze. Key Results Scopolamine (1.0 mg·kg −1 , i.p.) impaired short‐term memory performance in all three tests and this scopolamine‐induced amnesia was prevented by the A 2 A receptor antagonist ( SCH 58261, 0.1–1.0 mg·kg −1 , i.p.) and by the A 1 receptor antagonist ( DPCPX , 0.2–5.0 mg·kg −1 , i.p.), except in the modified Y ‐maze where only SCH58261 was effective. Both antagonists were devoid of effects on memory or locomotion in naïve rats. Notably, the activation of A 2 A receptors with CGS 21680 (0.1–0.5 mg·kg −1 , i.p.) before the training session was sufficient to trigger memory impairment in the three tests in naïve mice, and this effect was prevented by SCH 58261 (1.0 mg·kg −1 , i.p.). Furthermore, i.c.v. administration of CGS 21680 (50 nmol) also impaired recognition memory in the object recognition task. Conclusions and Implications These results show that A 2 A receptors are necessary and sufficient to trigger memory impairment and further suggest that A 1 receptors might also be selectively engaged to control the cholinergic‐driven memory impairment.