Adenosine A2A receptors are necessary and sufficient to trigger memory impairment in adult mice

Background and PurposeCaffeine (a non-selective adenosine receptor antagonist) prevents memory deficits in aging and Alzheimer's disease, an effect mimicked by adenosine A(2A) 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 ApproachWe determined whether A(2A) receptors are necessary for the emergence of memory impairments induced by scopolamine and whether A(2A) receptor activation triggers memory deficits in naive mice, using three tests to assess short-term memory, namely the object recognition task, inhibitory avoidance and modified Y-maze. Key ResultsScopolamine (1.0mgkg(-1), i.p.) impaired short-term memory performance in all three tests and this scopolamine-induced amnesia was prevented by the A(2A) receptor antagonist (SCH 58261, 0.1-1.0mgkg(-1), i.p.) and by the A(1) receptor antagonist (DPCPX, 0.2-5.0mgkg(-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 naive rats. Notably, the activation of A(2A) receptors with CGS 21680 (0.1-0.5mgkg(-1), i.p.) before the training session was sufficient to trigger memory impairment in the three tests in naive mice, and this effect was prevented by SCH 58261 (1.0mgkg(-1), i.p.). Furthermore, i.c.v. administration of CGS 21680 (50nmol) also impaired recognition memory in the object recognition task. Conclusions and ImplicationsThese results show that A(2A) 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.